Spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one compounds and derivatives as MDM2-P53 inhibitors

ABSTRACT

The present invention relates to compounds of formula (I) 
                         
wherein the groups R 1  to R 3 , R 7 , U, V, W, X, Y, n and q are as defined herein, their use as inhibitors of MDM2-p53 interaction, pharmaceutical compositions which contain compounds of this kind, their use as medicaments, especially as agents for treatment and/or prevention of oncological diseases and synthetic intermediates.

The present invention relates to newspiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one compounds and derivatives offormula (I)

wherein the groups R¹ to R³, R⁷, U, V, W, X, Y, n and q have themeanings as defined herein, their use as inhibitors of MDM2-p53interaction, pharmaceutical compositions which contain compounds of thiskind, their use as medicaments, especially as agents for treatmentand/or prevention of oncological diseases and synthetic intermediates.

BACKGROUND OF THE INVENTION

The tumor suppressor protein p53 is a sequence specific transcriptionfactor and plays a central role in the regulation of several cellularprocesses, including cell cycle and growth arrest, apoptosis, DNArepair, senescence, angiogenesis, and innate immunity. The Mouse DoubleMinute 2 (MDM2) protein (or its human homolog also known as HDM2) actsto down-regulate p53 activity in an auto-regulatory manner, and undernormal cellular conditions (absence of stress), the MDM2 protein servesto maintain p53 activity at low levels. MDM2 directly inhibits thetransactivation function of p53, exports p53 out of the nucleus, andpromotes proteasome-mediated degradation of p53 through its E3 ubiquitinligase activity.

Deregulation of the MDM2/p53 balance by overexpression of MDM2 or by p53mutation or loss leads to malignant transformation of normal cells.Presently p53 is known to play a key role in practically all types ofhuman cancers, and the mutation or loss of the p53 gene can beidentified in more than 50% of all human cancers worldwide. Analysis of28 different types of human cancers in nearly 4,000 human tumor samplesshowed that MDM2 is amplified in 7% of human cancers and that MDM2overexpression by amplification and p53 mutations are largely mutuallyexclusive (Momand et al., Nucleic Acid Res (1998) 26:3453-3459).

Because of the powerful tumor suppressor function of p53, reactivationof p53 has been long sought as a potentially novel cancer therapeuticstrategy. In tumor harboring wild-type p53, MDM2 is the primary cellularinhibitor of p53 activity, and overexpression of MDM2 was found in manyhuman tumors. Since MDM2 inhibits p53 through a direct protein-proteininteraction, blocking this interaction using small molecules was pursuedin several academic and industrial pharmaceutical laboratories in thelast decade. A variety of non-peptide, drug-like small molecule as e.g.imidazole compounds (e.g. Nutlins or RG7112), benzodiazepinedionecompounds, spirooxindole compounds (e.g. MI-219), substitutedpiperidines, pyrrolidinone compounds (e.g. PXN820-dl) and modificationsthereof have been selected and designed in order to block MDM2/p53interaction as a means to reactivate p53 in cells (Vassilev et al.,Science (2004) 303:844-848; Grasberger et al., J Med Chem (2005)48:909-912; Parks et al., Bioorg Med Chem Lett (2005) 15:765; Ding etal., J Am Soc (2005) 127:10130-10131; WO 2010/028862, U.S. Pat. No.7,884,107, WO 2008/119741). A number of potent MDM2/p53 inhibitors havebeen evaluated in animal models of human cancer for their anti-tumoractivity (Vassilev et al., Science (2004) 303:844-848; Tovar et al,Cancer Res (2013) 73 (8): 2587-2597; Ding et al, Journal of MedicinalChemistry (2013) 56 (14): 5979-5983; Rew et al, Journal of MedicinalChemistry (2012) 55: 4936-4954; Sun et al, Journal of MedicinalChemistry (2014) 57 (4): 1454-1472).

In the pediatric preclinical testing program (PPTP) of the NCI, earlyevidence for high level anti-proliferative activity of RG7112, aninhibitor of the MDM2-p53 interaction, could be observed in vitro and invivo. In particular, RG-7112 showed cytotoxic activity with lower medianIC₅₀ values for p53 wild-type vs. p53 mutant cell lines (Carol et al.,Pediatric Blood and Cancer (2013) 60(4):633-641). Moreover, RG-7112induced tumor growth inhibition in solid tumor xenograft models and wasparticularly efficacious in acute lymphoblastic leukemia (ALL) xenograftmodels with mixed-lineage leukemia (MLL) rearrangement, (Carol et al.,Pediatric Blood and Cancer (2013) 60(4):633-641). Additionally, theantiproliferative and proapoptotic activity of RG7112 has been observedin human acute myeloid leukemia (AML) and human prostate tumor xenograftmodels harboring p53 wild-type (Tovar et al, Cancer Res (2013) 73 (8):2587-2597).

Accordingly, small molecule inhibitors of the MDM2 protein interactionsoffer an important approach towards cancer therapy, either as a singleagent, or in combination with a broad variety of anti-tumor therapiesand thus, there is the need for further MDM2 inhibitors which can beuseful in the treatment of cancer.

The following prior art documents disclose spiro oxindole compounds asinhibitors of MDM2-p53 interaction:

WO 2007/104664; WO 2007/104714; WO 2008/141917; WO 2008/141975; WO2009/077357; WO 2009/080488; WO 2010/084097; WO 2010/121995; WO2011/067185; WO 2011/101297; WO 2011/134925; WO 2012/038307; WO2012/022707; WO 2012/116989; WO 2006/091646; WO 2008/036168; WO2011/060049; WO 2012/065022; WO 2012/155066; WO 2010/028862; WO2011/153509 and WO 2012/121361.

The aim of the present invention is to provide new compounds which canbe used for the prevention and/or treatment of a disease and/orcondition characterised by excessive or abnormal cell proliferation,especially a disease and/or condition wherein the inhibition of theinteraction between MDM2 and p53 is of therapeutic benefit.

The compounds according to the invention are characterised by a powerfulinhibitory effect on the interaction between MDM2 and p53 and in turn ahigh efficacy against tumour cells, e.g. osteosarcoma, ALL etc., whichis mediated through the inhibition of the interaction between MDM2 andp53. In addition to the inhibitory effect and cellular potency thecompounds show good PK properties and selectivity against p53 mutantcell lines. Furthermore, they have good metabolic stability and, incontrast to many compounds known in the prior art, good chemicalstability, i.e. they are for example less prone to epimerisation, aproblem identified for many known representatives of spiro oxindoles inthe prior art (see e.g. Zhao et al. J. Am. Chem. Soc 2013, 135,7223-7234; Shu et al. Org. Process Res. Dev. 2013, 17, 247-256; WO2012/065022).

DETAILED DESCRIPTION OF THE INVENTION

It has now been found that, surprisingly, compounds of formula (I)wherein the groups R¹ to R³, R⁷, U, V, W, X, Y, n and q have themeanings given hereinafter act as inhibitors of the interaction ofspecific proteins which are involved in controlling cell proliferation.Thus, the compounds according to the invention may be used for examplefor the treatment of diseases connected with this protein-proteininteraction and characterised by excessive or abnormal cellproliferation.

The present invention therefore relates to a compound of formula (I)

wherein[A0]R¹ is a group, optionally substituted by one or more, identical ordifferent R^(b1) and/or R^(c1), selected from among C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,C₄₋₆cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10 memberedheterocyclyl;

-   -   each R^(b1) is independently selected from among —OR^(c1),        —NR^(c1)R^(c1), halogen, —CN, —C(O)R^(c1), —C(O)OR^(c1),        —C(O)NR^(c1)R^(c1), —S(O)₂R^(c1), —S(O)₂NR^(c1)R^(c1),        —NHC(O)R^(c1) and —N(C₁₋₄alkyl)C(O)R^(c1);    -   each R^(c1) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(d1) and/or R^(e1), selected from among C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,        C₄₋₆cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10        membered heterocyclyl;    -   each R^(d1) is independently selected from among —OR^(e1),        —NR^(e1)R^(e1), halogen, —CN, —C(O)R^(e1), —C(O)OR^(e1),        —C(O)NR^(e1)R^(e1), —S(O)₂R^(e1), —S(O)₂NR^(e1)R^(e1),        —NHC(O)R^(e1) and —N(C₁₋₄alkyl)C(O)R^(e1);    -   each R^(e1) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(f1) and/or R^(g1), selected from among C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,        C₄₋₆cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10        membered heterocyclyl;    -   each R^(f1) is independently selected from among —OR^(g1),        —NR^(g1)R^(g1), halogen, —CN, —C(O) R^(g1), —C(O)OR^(g1),        —C(O)NR^(g1)R^(g1), —S(O)₂R^(g1), —S(O)₂NR^(g1)R^(g1),        —NHC(O)R^(g1) and —N(C₁₋₄alkyl)C(O)R^(g1);    -   each R^(g1) is independently selected from among hydrogen,        C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,        C₃₋₆cycloalkyl, C₄₋₆cycloalkenyl, C₆₋₁₀aryl, 5-10 membered        heteroaryl and 3-10 membered heterocyclyl;        [B0]        R² and R³, each independently, is selected from among hydrogen,        C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10 membered        heterocyclyl, wherein this C₆₋₁₀aryl, 5-10 membered heteroaryl        and 3-10 membered heterocyclyl is optionally substituted by one        or more, identical or different R^(b2) and/or R^(c2);    -   each R^(b2) is independently selected from among —OR^(c2),        —NR^(c2)R^(c2), halogen, —CN, —C(O)R^(c2), —C(O)OR^(c2),        —C(O)NR^(c2)R^(c2), —S(O)₂R^(c2), —S(O)₂NR^(c2)R^(c2),        —NHC(O)R^(c2) and —N(C₁₋₄alkyl)C(O)R^(c2);    -   each R^(c2) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(d2) and/or R^(e2), selected from among C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,        C₄₋₆cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10        membered heterocyclyl;    -   each R^(d2) is independently selected from among —OR^(e2),        —NR^(e2)R^(e2), halogen, —CN, —C(O)R^(e2), —C(O)OR^(e2),        —C(O)NR^(e2)R^(e2), —S(O)₂R^(e2), —S(O)₂NR^(e2)R^(e2),        —NHC(O)R^(e2) and —N(C₁₋₄alkyl)C(O)R^(e2);    -   each R^(e2) independently of one another denotes hydrogen or a        group selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₄₋₆cycloalkenyl, C₆₋₁₀aryl, 5-10        membered heteroaryl and 3-10 membered heterocyclyl;        [C0]        U is selected from among —O— and —NR⁵—;        R⁵ is hydrogen or a group, optionally substituted by one or        more, identical or different R^(b4) and/or R^(c4), selected from        among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,        C₃₋₆cycloalkyl, C₄₋₆cycloalkenyl, C₆₋₁₀aryl, 5-10 membered        heteroaryl and 3-10 membered heterocyclyl;    -   each R^(b4) is independently selected from among —OR^(c4),        —NR^(c4)R^(c4), halogen, —CN, —NO₂, —C(O)R^(c4), —C(O)OR^(c4),        —C(O)NR^(c4)R^(c4), —C(O)NR^(g4)OR^(c4), —C(O)C(O)OR^(c4),        —S(O)₂R^(c4), —S(O)₂NR^(c4)R^(c4), —NHSO₂R^(c4),        —N(C₁₋₄alkyl)SO₂R^(c4), —NHC(O)R^(c4) and —N(C₁₋₄alkyl)C(O)        R^(c4);    -   each R^(c4) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(d4) and/or R^(e4), selected from among C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,        C₄₋₆cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10        membered heterocyclyl;    -   each R^(d4) is independently selected from among —OR^(e4),        —NR^(e4)R^(e4), halogen, —CN, —C(O)R^(e4), —C(O)OR^(e4),        —C(O)NR^(e4)R^(e4), —C(O)NR^(g4)OR^(e4), —OC(O)R^(e4),        —S(O)₂R^(e4), —S(O)₂NR^(e4)R^(e4), —NHC(O)R^(e4) and        —N(C₁₋₄alkyl)C(O)R^(e4);    -   each R^(e4) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(f4) and/or R^(g4), selected from among C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,        C₄₋₆cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10        membered heterocyclyl;    -   each R^(f4) is independently selected from among —OR^(g4),        —NR^(g4)R^(g4), halogen, —CN, —C(O)R^(g4), —C(O)OR^(g4),        —C(O)NR^(g4)R^(g4), —C(O)NR^(g4) OR^(g4), —S(O)₂R^(g4),        —S(O)₂NR^(g4)R^(g4), —NHC(O)R^(g4) and —N(C₁₋₄alkyl)C(O)R^(g4);    -   each R^(g4) is independently selected from among hydrogen,        C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,        C₃₋₆cycloalkyl, C₄₋₆cycloalkenyl, C₆₋₁₀aryl, 5-10 membered        heteroaryl and 3-10 membered heterocyclyl;        [D0]        each R⁷ is independently selected from among halogen, C₁₋₄alkyl,        —CN, C₁₋₄haloalkyl, —OC₁₋₄alkyl and —OC₁₋₄haloalkyl;        q denotes the number 0, 1, 2 or 3;        [E0]        W, X and Y is each independently selected from —N═ and —CH═ with        the proviso that the hydrogen in each —CH═ may be replaced by a        substituent R⁷ if present and that a maximum of two of W, X and        Y can be —N═;        [F0]        V is oxygen or sulfur;        [G0]        n denotes the number 1, 2 or 3;        or a salt thereof.

In one aspect the invention relates to the compound of formula (Ia)

or a salt thereof, wherein the groups R¹ to R³, R⁷, U, V, W, X, Y, n andq are defined as for formula (I).

In another aspect the invention relates to the compound of formula (Ib)

or a salt thereof, wherein the groups R¹ to R³, R⁷, U, V, W, X, Y, n andq are defined as for formula (I).

It is to be understood that compounds (Ia) are a subset of compounds (I)and that whenever the term “compound(s) (I)” is used this also includescompound(s) (Ia) unless stated otherwise.

It is to be understood that compounds (I) and compounds (Ia) are asubset of compounds (Ib) and that whenever the term “compound(s) (Ib)”is used this also includes compound(s) (I) and compounds (Ia) unlessstated otherwise.

In another aspect [A1] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

R¹ is C₁₋₆alkyl, optionally substituted by a group selected from amongC₃₋₆cycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl, wherein thisC₃₋₆cycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl is optionallysubstituted by one or more, identical or different R^(d1) and/or R^(e1);

-   -   each R^(d1) is independently selected from among —OR^(e1),        —NR^(e1)R^(e1), halogen, —CN, —C(O)R^(e1), —C(O)OR^(e1),        —C(O)NR^(e1)R^(e1), —S(O)₂R^(e1), —S(O)₂NR^(e1)R^(e1),        —NHC(O)R^(e1) and —N(C₁₋₄alkyl)C(O)R^(e1);    -   each R^(e1) independently of one another denotes hydrogen or a        group selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₄₋₆cycloalkenyl, C₆₋₁₀aryl, 5-10        membered heteroaryl and 3-10 membered heterocyclyl; or        R¹ is selected from among C₁₋₆alkoxy-C₁₋₆alkyl and        C₁₋₆haloalkyl;        or a salt thereof.

In another aspect [A2] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

R¹ is C₁₋₆alkyl, optionally substituted by a group selected from amongC₃₋₆cycloalkyl, phenyl and 5-6 membered heteroaryl, wherein thisC₃₋₆cycloalkyl, phenyl and 5-6 membered heteroaryl is optionallysubstituted by one or more, identical or different R^(d1) and/or R^(e1);

-   -   each R^(d1) is independently selected from among —OR^(e1),        —NR^(e1)R^(e1), halogen, —CN, —C(O)R^(e1), —C(O)OR^(e1),        —C(O)NR^(e1)R^(e1), —S(O)₂R^(e1), —S(O)₂NR^(e1)R^(e1),        —NHC(O)R^(e1) and —N(C₁₋₄alkyl)C(O)R^(e1);    -   each R^(e1) independently of one another denotes hydrogen or a        group selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₄₋₆cycloalkenyl, phenyl, 5-6        membered heteroaryl and 3-7 membered heterocyclyl; or        R¹ is selected from among C₁₋₆alkoxy-C₁₋₆alkyl and        C₁₋₆haloalkyl;        or a salt thereof.

In another aspect [A3] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

R¹ is C₁₋₆alkyl, optionally substituted by a group selected from amongC₃₋₆cycloalkyl, phenyl and 5-6 membered heteroaryl, wherein thisC₃₋₆cycloalkyl, phenyl and 5-6 membered heteroaryl is optionallysubstituted by one or more, identical or different substituents selectedfrom among —OC₁₋₆alkyl, halogen, C₁₋₆alkyl and C₁₋₆haloalkyl; orR¹ is selected from among C₁₋₆alkoxy-C₁₋₆alkyl and C₁₋₆haloalkyl;or a salt thereof.

In another aspect [A4] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

R¹ is C₃₋₆cycloalkyl-C₁₋₆alkyl;

or a salt thereof.

In another aspect [A5] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

R¹ is cyclopropylmethyl;

or a salt thereof.

In another aspect [A6] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

R¹ is benzyl, optionally substituted on the phenyl ring by one or more,identical or different R^(d1) and/or R^(e1);

-   -   each R^(d1) is independently selected from among —OR^(e1),        —NR^(e1)R^(e1), halogen, —CN, —C(O)R^(e1), —C(O)OR^(e1),        —C(O)NR^(e1)R^(e1), —S(O)₂R^(e1), —S(O)₂NR^(e1)R^(e1),        —NHC(O)R^(e1) and —N(C₁₋₄alkyl)C(O)R^(e1);    -   each R^(e1) independently of one another denotes hydrogen or a        group selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₄₋₆cycloalkenyl, phenyl, 5-6        membered heteroaryl and 3-7 membered heterocyclyl;        or a salt thereof.

In another aspect [A7] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

R¹ is 3-ethoxybenzyl;

or a salt thereof.

In another aspect [A8] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

R¹ is C₁₋₆alkyl;

or a salt thereof.

In another aspect [B1] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

one of R² and R³ is hydrogen and the other is selected from among phenyland 5-6 membered heteroaryl, wherein this phenyl and 5-6 memberedheteroaryl is optionally substituted by one or more, identical ordifferent R^(b2) and/or R^(c2);

-   -   each R^(b2) is independently selected from among —OR^(c2),        —NR^(c2)R^(c2), halogen, —CN, —C(O)R^(c2), —C(O)OR^(c2),        —C(O)NR^(c2)R^(c2), —S(O)₂R^(c2), —S(O)₂NR^(c2)R^(c2),        —NHC(O)R^(c2) and —N(C₁₋₄alkyl)C(O)R^(c2);    -   each R^(c2) independently of one another denotes hydrogen or a        group selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₄₋₆cycloalkenyl, phenyl, 5-6        membered heteroaryl and 3-7 membered heterocyclyl;        or a salt thereof.

In another aspect [B2] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

one of R² and R³ is hydrogen and the other is phenyl optionallysubstituted by one or more, identical or different substituents selectedfrom among —OC₁₋₆alkyl, halogen, C₁₋₆alkyl and C₁₋₆haloalkyl;

or a salt thereof.

In another aspect [B3] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

one of R² and R³ is hydrogen and the other is selected from among3-chloro phenyl, 3-chloro 2-fluoro phenyl and 3-bromo 2-fluoro phenyl;

or a salt thereof.

In further aspects [B4], [B5], [B6] and [B7] the invention relates to acompound of formula (I) or (Ia) or (Ib) with structural aspects [B0],[B1], [B2] and [B3], wherein

R³ is hydrogen;

or a salt thereof.

In further aspects [B8], [B9], [B10] and [B11] the invention relates toa compound of formula (I) or (Ia) or (Ib) with structural aspects [B0],[B1], [B2] and [B3], wherein

R² is hydrogen;

or a salt thereof.

In another aspect [C1] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

U is —O—;

or a salt thereof.

In another aspect [C2] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

U is —NH—;

or a salt thereof.

In another aspect [C3] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

U is —NR⁵—;

R⁵ is a group, optionally substituted by one or more, identical ordifferent R^(b4) and/or R^(c4), selected from among C₁₋₆alkyl, C₆₋₁₀aryland 5-10 membered heteroaryl;

-   -   each R^(b4) is independently selected from among —OR^(c4),        —NR^(c4)R^(c4), halogen, —CN, —NO₂, —C(O)R^(c4), —C(O)OR^(c4),        —C(O)NR^(c4)R^(c4), —C(O)NR^(e4) OR^(c4), —C(O)C(O)OR^(c4),        —S(O)₂R^(c4), —S(O)₂NR^(c4)R^(c4), —NHSO₂R^(c4),        —N(C₁₋₄alkyl)SO₂R^(c4), —NHC(O)R^(c4) and —N(C₁₋₄alkyl)C(O)        R^(c4);    -   each R^(c4) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(d4) and/or R^(e4), selected from among C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5-10 membered        heteroaryl and 3-10 membered heterocyclyl;    -   each R^(d4) is independently selected from among —OR^(e4),        —NR^(e4)R^(e4), halogen, —CN, —C(O)R^(e4), —C(O)OR^(e4),        —C(O)NR^(e4)R^(e4), —C(O)NR^(e4) OR^(e4),    -   —OC(O)R^(e4), —S(O)₂R^(e4), —S(O)₂NR^(e4)R^(e4), —NHC(O)R^(e4)        and —N(C₁₋₄alkyl)C(O)R^(e4);    -   each R^(e4) independently of one another is selected from among        hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5-10 membered        heteroaryl and 3-10 membered heterocyclyl;        or a salt thereof.

In another aspect [C4] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

U is —NR⁵—;

R⁵ is a group, optionally substituted by one or more, identical ordifferent R^(b4) and/or R^(c4), selected from among C₁₋₆alkyl, phenyland 5-6 membered heteroaryl;

-   -   each R^(b4) is independently selected from among —OR^(c4),        —NR^(c4)R^(c4), halogen, —CN, —NO₂, —C(O)R^(c4), —C(O)OR^(c4),        —C(O)NR^(c4)R^(c4), —C(O)NR^(e4) OR^(c4), —C(O)C(O)OR^(c4),        —S(O)₂R^(c4), —S(O)₂NR^(c4)R^(c4), —NHSO₂R^(c4),        —N(C₁₋₄alkyl)SO₂R^(c4), —NHC(O)R^(c4) and —N(C₁₋₄alkyl)C(O)        R^(c4);    -   each R^(c4) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(d4) and/or R^(e4), selected from among C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl        and 3-7 membered heterocyclyl;    -   each R^(d4) is independently selected from among —OR^(e4),        —NR^(e4)R^(e4) halogen, —CN, —C(O)R^(e4), —C(O)OR^(e4),        —C(O)NR^(e4)R^(e4), —C(O)NR^(e4) OR^(e4), —OC(O)R^(e4),        —S(O)₂R^(e4), —S(O)₂NR^(e4)R^(e4), —NHC(O)R^(e4) and        —N(C₁₋₄alkyl)C(O)R^(e4);    -   each R^(e4) independently of one another is selected from among        hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered        heteroaryl and 3-7 membered heterocyclyl;        or a salt thereof.

In another aspect [C5] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

U is —NR⁵—;

R⁵ is a group, optionally substituted by one or more, identical ordifferent R^(b4) and/or R^(c4), selected from among C₁₋₆alkyl, phenyland 5-6 membered heteroaryl;

-   -   each R^(b4) is independently selected from among —OR^(c4),        —NR^(c4)R^(c4), halogen, —CN, —C(O)R^(c4), —C(O)OR^(c4),        —C(O)NR^(c4)R^(c4), —C(O)NR^(e4)OR^(c4), —C(O)C(O)OR^(c4),        —S(O)₂R^(c4), —S(O)₂NR^(c4)R^(c4), —NHSO₂R^(c4),        —N(C₁₋₄alkyl)SO₂R^(c4), —NHC(O)R^(c4) and        —N(C₁₋₄alkyl)C(O)R^(c4);    -   each R^(c4) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(d4) and/or R^(e4), selected from among C₁₋₆alkyl,        C₁₋₆haloalkyl, phenyl and 5-6 membered heteroaryl;    -   each R^(d4) is independently selected from among —OR^(e4),        —C(O)OR^(e4), —OC(O)R^(e4) and —C(O)NR^(e4)R^(e4);    -   each R^(e4) independently of one another is selected from among        hydrogen and C₁₋₆alkyl;        or a salt thereof.

In another aspect [C6] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

U is —NR⁵—;

R⁵ is phenyl optionally substituted by one or more, identical ordifferent substituents selected from among C₁₋₆alkyl, C₁₋₆haloalkyl,—OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halogen, —C(O)OH, —C(O)OC₁₋₆alkyl,—C(O)NH₂, —C(O)NHC₁₋₆alkyl and —C(O)N(C₁₋₆alkyl)₂;

or a salt thereof.

In another aspect [C7] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

U is —NR⁵—;

R⁵ is

R⁸ is selected from among C₁₋₆alkyl, C₁₋₆haloalkyl, —OC₁₋₆alkyl,—OC₁₋₆haloalkyl and halogen;R⁹ is selected from among —C(O)OH, —C(O)OC₁₋₆alkyl, —C(O)NH₂,—C(O)NHC₁₋₆alkyl and —C(O)N(C₁₋₆alkyl)₂;or a salt thereof.

In another aspect [D1] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

each R⁷ independently is halogen and q is 1 or 2;

or a salt thereof.

In another aspect [D2] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

each R⁷ independently is chlorine or fluorine and q is 1 or 2;

or a salt thereof.

In another aspect [E1] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

W, X and Y are —CH═

with the proviso that the hydrogen in each —CH═ may be replaced by asubstituent R⁷ if present;

or a salt thereof.

In another aspect [F1] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

V is oxygen;

or a salt thereof.

In another aspect [G1] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

n is 1;

or a salt thereof.

In another aspect [G2] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein

n is 2;

or a salt thereof.

In another aspect [DE1] the invention relates to a compound of formula(I) or (Ia) or (Ib), wherein the 6-membered ring comprising W, X and Ytogether with the q substituents R⁷ has a substructure selected fromamong (i) and (ii)

or a salt thereof.

All the above-mentioned structural aspects A1 to A8, B1 to B11, C1 toC7, D1 and D2, E1, F1, G1 and G2 and DE1 are preferred embodiments ofthe corresponding aspects A0, B0, C0, D0, E0, DE0, F0 and G0,respectively, wherein DE0 (DE) represents the combination of D0 (D) andE0 (E). The structural aspects A0 to A8, B0 to B11, C0 to C7, D0 to D2,E0 and E1, F0 and F1, DE1 and G0 to G2 relating to different molecularparts of the compounds (I), (Ia) and (Ib) according to the invention maybe permutated with one another as desired in combinations ABCDEFG, so asto obtain preferred compounds (I), (Ia) and (Ib) (aspects D and E can bereplaced by combination aspect DE). Each combination ABCDEFG representsand defines individual embodiments or generic subsets of compoundsaccording to the invention.

Preferred embodiments of the invention are example compounds I-1 toI-307.

All synthetic intermediates disclosed herein are also part of theinvention.

Compounds (I) according to the invention may also serve as valuableintermediates towards additional spiro oxindole inhibitors of MDM2-p53interaction which are different from formula (I).

In a further aspect the invention also relates to syntheticintermediates of formula A-6 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (I) or (Ia) or(Ib):

The definitions of groups R², R³, R⁷, U, V, W, X, Y, n and q in A-6correspond to those as given for compound (I) and (Ia) and (Ib) above,i.e. [B0] for R²/R³, [C0] for U, [D0] for R⁷/q, [E0] for W/X/Y, [F0] forV and [G0] for n.

Preferred intermediates A-6 are those which lead to preferred compounds(I) or (Ia) or (Ib) according to the invention, i.e. preferredembodiments of A-6 have structural aspects selected from [B0] to [B11]for R²/R³, [C0] to [C7] for U, [D0] to [D2] for R⁷/q, [E0] and [E1] forW/X/Y, [F0] and [F1] for V, [G0] to [G2] for n, [DE1] for R⁷/q/W/X/Yaltogether. These structural aspects may be permutated with one anotheras desired in combinations BCDEFG, so as to obtain preferredintermediates A-6 (aspects D and E can be replaced by combination aspectDE). Each combination BCDEFG represents and defines individualembodiments or generic subsets of intermediates A-6.

In a further aspect the invention also relates to the use of syntheticintermediates of formula A-6 or their salts (and the various embodimentsand sub-groups as described and/or defined herein) in the synthesis ofcompounds (I) or (Ia) or (Ib).

The present invention further relates to hydrates, solvates, polymorphs,metabolites, derivatives, isomers and prodrugs of a compound of formula(I) or (Ia) or (Ib).

Compounds of formula (I) or (Ia) or (Ib) which e.g. bear ester groupsare potential prodrugs the ester being cleaved under physiologicalconditions.

The present invention further relates to a pharmaceutically acceptablesalt of a compound of formula (I) or (Ia) or (Ib).

The present invention further relates to a pharmaceutically acceptablesalt of a compound of formula (I) or (Ia) or (Ib) with anorganic ororganic acids or bases.

The present invention is directed to compounds of formula (I) or (Ia) or(Ib) which are useful in the prevention and/or treatment of a diseaseand/or condition wherein the inhibition of the interaction between MDM2and p53 is of therapeutic benefit, including but not limited to thetreatment and/or prevention of cancer.

In another aspect the invention relates to a compound of formula (I) or(Ia) or (Ib)—or a pharmaceutically acceptable salt thereof—for use asmedicament.

In another aspect the invention relates to a compound of formula (I) or(Ia) or (Ib)—or a pharmaceutically acceptable salt thereof—for use in amethod for treatment of the human or animal body.

In another aspect the invention relates to a compound of formula (I) or(Ia) or (Ib)—or a pharmaceutically acceptable salt thereof—for use inthe treatment and/or prevention of a disease and/or condition whereinthe inhibition of the interaction between MDM2 and p53 is of therapeuticbenefit.

In another aspect the invention relates to a compound of formula (I) or(Ia) or (Ib)—or a pharmaceutically acceptable salt thereof—for use inthe treatment and/or prevention of cancer, infections, inflammations andautoimmune diseases.

In another aspect the invention relates to a compound of formula (I) or(Ia) or (Ib)—or a pharmaceutically acceptable salt thereof—for use in amethod for treatment and/or prevention of cancer, infections,inflammations and autoimmune diseases in the human and animal body.

In another aspect the invention relates to the use of a compound offormula (I) or (Ia) or (Ib)—or a pharmaceutically acceptable saltthereof—for preparing a pharmaceutical composition for the treatmentand/or prevention of cancer, infections, inflammations and autoimmunediseases.

In another aspect the invention relates to a compound of formula (I) or(Ia) or (Ib)—or a pharmaceutically acceptable salt thereof—for use inthe treatment and/or prevention of cancer.

In another aspect the invention relates to the use of a compound offormula (I) or (Ia) or (Ib)—or a pharmaceutically acceptable saltthereof—for preparing a pharmaceutical composition for the treatmentand/or prevention of cancer.

In another aspect the invention relates to a compound of formula (I) or(Ia) or (Ib)—or a pharmaceutically acceptable salt thereof—for use in amethod for treatment and/or prevention of cancer in the human or animalbody.

In another aspect the invention relates to a compound of formula (I) or(Ia) or (Ib)—or a pharmaceutically acceptable salt thereof—for use inthe treatment and/or prevention of acute myeloid leukaemia (AML),prostate cancer and lung cancer, wherein the cancer cells are p53wild-type.

In another aspect the invention relates to a compound of formula (I) or(Ia) or (Ib)—or a pharmaceutically acceptable salt thereof—for use inthe treatment and/or prevention of acute myeloid leukaemia (AML),prostate cancer and lung cancer, wherein the cancer cells are preferablyp53 wild-type.

In another aspect the invention relates to the use of a compound offormula (I) or (Ia) or (Ib)—or a pharmaceutically acceptable saltthereof—for preparing a pharmaceutical composition for the treatmentand/or prevention of acute myeloid leukaemia (AML), prostate cancer andlung cancer, wherein the cancer cells are p53 wild-type.

In another aspect the invention relates to the use of a compound offormula (I) or (Ia) or (Ib)—or a pharmaceutically acceptable saltthereof—for preparing a pharmaceutical composition for the treatmentand/or prevention of acute myeloid leukaemia (AML), prostate cancer andlung cancer, wherein the cancer cells are preferably p53 wild-type.

In another aspect the invention relates to a method for the treatmentand/or prevention of a disease and/or condition wherein the inhibitionof the interaction between MDM2 and p53 is of therapeutic benefitcomprising administering a therapeutically effective amount of acompound of formula (I) or (Ia) or (Ib)—or a pharmaceutically acceptablesalt thereof—to a human being.

In another aspect the invention relates to a method for the treatmentand/or prevention of cancer comprising administering a therapeuticallyeffective amount of a compound of formula (I) or (Ia) or (Ib)—or apharmaceutically acceptable salt thereof—to a human being.

In another aspect the invention relates to a pharmaceutical compositioncomprising at least one compound of formula (I) or (Ia) or (Ib)—or apharmaceutically acceptable salt thereof—and a pharmaceuticallyacceptable carrier.

In another aspect the invention relates to a pharmaceutical preparationcomprising a compound of formula (I) or (Ia) or (Ib)—or apharmaceutically acceptable salt thereof—and at least one othercytostatic or cytotoxic active substance, different from formula (I) or(Ia) or (Ib).

In another aspect the invention relates to a compound of formula (I) or(Ia) or (Ib)—or a pharmaceutically acceptable salt thereof—for use inthe treatment and/or prevention of cancer, infections, inflammations andautoimmune diseases wherein said compound is administered before, afteror together with at least one other cytostatic or cytotoxic activesubstance.

In another aspect the invention relates to the use of a compound offormula (I) or (Ia) or (Ib)—or a pharmaceutically acceptable saltthereof—for preparing a medicament for the treatment and/or preventionof cancer, infections, inflammations and autoimmune diseases whereinsaid compound is administered before, after or together with at leastone other cytostatic or cytotoxic active substance.

In another aspect the invention relates to a cytostatic or cytotoxicactive substance prepared for being administered before, after ortogether with a compound of formula (I) or (Ia) or (Ib)—or apharmaceutically acceptable salt thereof—for use in the treatment and/orprevention of cancer, infections, inflammations and autoimmune diseases.

In another aspect the invention relates to a method for the treatmentand/or prevention of cancer, infections, inflammations and autoimmunediseases comprising administering a therapeutically effective amount ofa compound of formula (I) or (Ia) or (Ib)—or a pharmaceuticallyacceptable salt thereof—before, after or together with at least oneother cytostatic or cytotoxic active substance to a human being.

Definitions

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to:

The use of the prefix C_(x-y), wherein x and y each represent a naturalnumber (x<y), indicates that the chain or ring structure or combinationof chain and ring structure as a whole, specified and mentioned indirect association, may consist of a maximum of y and a minimum of xcarbon atoms.

The indication of the number of members in groups that contain one ormore heteroatom(s) (e.g. heteroalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocycylalkyl) relates to the total number of atoms ofall the ring members or chain members or the total of all the ring andchain members.

The indication of the number of carbon atoms in groups that consist of acombination of carbon chain and carbon ring structure (e.g.cycloalkylalkyl, arylalkyl) relates to the total number of carbon atomsof all the carbon ring and carbon chain members. Obviously, a ringstructure has at least three members.

In general, for groups comprising two or more subgroups (e.g.heteroarylalkyl, heterocycylalkyl, cycloalkylalkyl, arylalkyl) the lastnamed subgroup is the radical attachment point, for example, thesubstituent aryl-C₁₋₆alkyl means an aryl group which is bound to aC₁₋₆alkyl group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

Alkyl denotes monovalent, saturated hydrocarbon chains, which may bepresent in both straight-chain (unbranched) and branched form. If analkyl is substituted, the substitution may take place independently ofone another, by mono- or polysubstitution in each case, on all thehydrogen-carrying carbon atoms.

The term “C₁₋₅alkyl” includes for example H₃C—, H₃C—CH₂—, H₃C—CH₂—CH₂—,H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—, H₃C—CH(CH₃)—CH₂—,H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—, H₃C—CH₂—CH₂—CH(CH₃)—,H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—, H₃C—CH₂—C(CH₃)₂—,H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— and H₃C—CH₂—CH(CH₂CH₃)—.

Further examples of alkyl are methyl (Me; —CH₃), ethyl (Et; —CH₂CH₃),1-propyl (n-propyl; n-Pr; —CH₂CH₂CH₃), 2-propyl (i-Pr; iso-propyl;—CH(CH₃)₂), 1-butyl (n-butyl; n-Bu; —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl(iso-butyl; i-Bu; —CH₂CH(CH₃)₂), 2-butyl (sec-butyl; sec-Bu;—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (tert-butyl; t-Bu; —C(CH₃)₃),1-pentyl (n-pentyl; —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃),3-pentyl (—CH(CH₂CH₃)₂), 3-methyl-1-butyl (iso-pentyl; —CH₂CH₂CH(CH₃)₂),2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂),2,2-dimethyl-1-propyl (neo-pentyl; —CH₂C(CH₃)₃), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (n-hexyl; —CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃), 2,3-dimethyl-1-butyl(—CH₂CH(CH₃)CH(CH₃)CH₃), 2,2-dimethyl-1-butyl (—CH₂C(CH₃)₂CH₂CH₃),3,3-dimethyl-1-butyl (—CH₂CH₂C(CH₃)₃), 2-methyl-1-pentyl(—CH₂CH(CH₃)CH₂CH₂CH₃), 3-methyl-1-pentyl (—CH₂CH₂CH(CH₃)CH₂CH₃),1-heptyl (n-heptyl), 2-methyl-1-hexyl, 3-methyl-1-hexyl,2,2-dimethyl-1-pentyl, 2,3-dimethyl-1-pentyl, 2,4-dimethyl-1-pentyl,3,3-dimethyl-1-pentyl, 2,2,3-trimethyl-1-butyl, 3-ethyl-1-pentyl,1-octyl (n-octyl), 1-nonyl (n-nonyl); 1-decyl (n-decyl) etc.

By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyletc. without any further definition are meant saturated hydrocarbongroups with the corresponding number of carbon atoms, wherein allisomeric forms are included.

The above definition for alkyl also applies if alkyl is a part ofanother (combined) group such as for example C_(x-y)alkylamino orC_(x-y)alkyloxy.

The term alkylene can also be derived from alkyl. Alkylene is bivalent,unlike alkyl, and requires two binding partners. Formally, the secondvalency is produced by removing a hydrogen atom in an alkyl.Corresponding groups are for example —CH₃ and —CH₂—, —CH₂CH₃ and—CH₂CH₂— or >CHCH₃ etc.

The term “C₁₋₄alkylene” includes for example —(CH₂)—, —(CH₂—CH₂)—,—(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—,—(CH(CH₃)—CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—CH₂—CH₂—CH₂)—,—(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—CH₂—CH₂)—, —(CH₂—CH(CH₃)—CH₂)—,—(CH₂—C(CH₃)₂)—, —(C(CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—,—(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—CH₂)—, —(CH(CH₂CH₂CH₃))—,—(CH(CH(CH₃))₂)— and —C(CH₃)(CH₂CH₃)—.

Other examples of alkylene are methylene, ethylene, propylene,1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene,1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene,2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene,hexylene etc.

By the generic terms propylene, butylene, pentylene, hexylene etc.without any further definition are meant all the conceivable isomericforms with the corresponding number of carbon atoms, i.e. propyleneincludes 1-methylethylene and butylene includes 1-methylpropylene,2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene.

The above definition for alkylene also applies if alkylene is part ofanother (combined) group such as for example in HO—C_(x-y)alkyleneaminoor H₂N—C_(x-y)alkyleneoxy.

Unlike alkyl, alkenyl consists of at least two carbon atoms, wherein atleast two adjacent carbon atoms are joined together by a C—C double bondand a carbon atom can only be part of one C—C double bond. If in analkyl as hereinbefore defined having at least two carbon atoms, twohydrogen atoms on adjacent carbon atoms are formally removed and thefree valencies are saturated to form a second bond, the correspondingalkenyl is formed.

Examples of alkenyl are vinyl (ethenyl), prop-1-enyl, allyl(prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl,2-methyl-prop-2-enyl, 2-methyl-prop-1-enyl, 1-methyl-prop-2-enyl,1-methyl-prop-1-enyl, 1-methylidenepropyl, pent-1-enyl, pent-2-enyl,pent-3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl,3-methyl-but-1-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl,hex-5-enyl, 2,3-dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl,2-methylidene-3-methylbutyl, 2,3-dimethyl-but-1-enyl, hexa-1,3-dienyl,hexa-1,4-dienyl, penta-1,4-dienyl, penta-1,3-dienyl, buta-1,3-dienyl,2,3-dimethylbuta-1,3-diene etc.

By the generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl,pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyletc. without any further definition are meant all the conceivableisomeric forms with the corresponding number of carbon atoms, i.e.propenyl includes prop-1-enyl and prop-2-enyl, butenyl includesbut-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1-enyl,1-methyl-prop-2-enyl etc.

Alkenyl may optionally be present in the cis or trans or E or Zorientation with regard to the double bond(s).

The above definition for alkenyl also applies when alkenyl is part ofanother (combined) group such as for example in C_(x-y)alkenylamino orC_(x-y)alkenyloxy.

Unlike alkylene, alkenylene consists of at least two carbon atoms,wherein at least two adjacent carbon atoms are joined together by a C—Cdouble bond and a carbon atom can only be part of one C—C double bond.If in an alkylene as hereinbefore defined having at least two carbonatoms, two hydrogen atoms at adjacent carbon atoms are formally removedand the free valencies are saturated to form a second bond, thecorresponding alkenylene is formed.

Examples of alkenylene are ethenylene, propenylene, 1-methylethenylene,butenylene, 1-methylpropenylene, 1,1-dimethylethenylene,1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene,2,2-dimethylpropenylene, 1,2-dimethylpropenylene,1,3-dimethylpropenylene, hexenylene etc.

By the generic terms propenylene, butenylene, pentenylene, hexenyleneetc. without any further definition are meant all the conceivableisomeric forms with the corresponding number of carbon atoms, i.e.propenylene includes 1-methylethenylene and butenylene includes1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylethenylene and1,2-dimethylethenylene.

Alkenylene may optionally be present in the cis or trans or E orZorientation with regard to the double bond(s).

The above definition for alkenylene also applies when alkenylene is apart of another (combined) group as for example inHO—C_(x-y)alkenyleneamino or H₂N—C_(x-y)alkenyleneoxy.

Unlike alkyl, alkynyl consists of at least two carbon atoms, wherein atleast two adjacent carbon atoms are joined together by a C—C triplebond. If in an alkyl as hereinbefore defined having at least two carbonatoms, two hydrogen atoms in each case at adjacent carbon atoms areformally removed and the free valencies are saturated to form twofurther bonds, the corresponding alkynyl is formed.

Examples of alkynyl are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl,but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl, pent-1-ynyl, pent-2-ynyl,pent-3-ynyl, pent-4-ynyl, 3-methyl-but-1-ynyl, hex-1-ynyl, hex-2-ynyl,hex-3-ynyl, hex-4-ynyl, hex-5-ynyl etc.

By the generic terms propynyl, butynyl, pentynyl, hexynyl, heptynyl,octynyl, nonynyl, decynyl etc. without any further definition are meantall the conceivable isomeric forms with the corresponding number ofcarbon atoms, i.e. propynyl includes prop-1-ynyl and prop-2-ynyl,butynyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl,1-methyl-prop-1-ynyl, 1-methyl-prop-2-ynyl, etc.

If a hydrocarbon chain carries both at least one double bond and also atleast one triple bond, by definition it belongs to the alkynyl subgroup.

The above definition for alkynyl also applies if alkynyl is part ofanother (combined) group, as for example in C_(x-y)alkynylamino orC_(x-y)alkynyloxy.

Unlike alkylene, alkynylene consists of at least two carbon atoms,wherein at least two adjacent carbon atoms are joined together by a C—Ctriple bond. If in an alkylene as hereinbefore defined having at leasttwo carbon atoms, two hydrogen atoms in each case at adjacent carbonatoms are formally removed and the free valencies are saturated to formtwo further bonds, the corresponding alkynylene is formed.

Examples of alkynylene are ethynylene, propynylene, 1-methylethynylene,butynylene, 1-methylpropynylene, 1,1-dimethylethynylene,1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene,2,2-dimethylpropynylene, 1,2-dimethylpropynylene,1,3-dimethylpropynylene, hexynylene etc.

By the generic terms propynylene, butynylene, pentynylene, hexynyleneetc. without any further definition are meant all the conceivableisomeric forms with the corresponding number of carbon atoms, i.e.propynylene includes 1-methylethynylene and butynylene includes1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and1,2-dimethylethynylene.

The above definition for alkynylene also applies if alkynylene is partof another (combined) group, as for example in HO—C_(x-y)alkynyleneaminoor H₂N—C_(x-y)alkynyleneoxy.

By heteroatoms are meant oxygen, nitrogen and sulphur atoms.

Haloalkyl (haloalkenyl, haloalkynyl) is derived from the previouslydefined alkyl (alkenyl, alkynyl) by replacing one or more hydrogen atomsof the hydrocarbon chain independently of one another by halogen atoms,which may be identical or different. If a haloalkyl (haloalkenyl,haloalkynyl) is to be further substituted, the substitutions may takeplace independently of one another, in the form of mono- orpolysubstitutions in each case, on all the hydrogen-carrying carbonatoms.

Examples of haloalkyl (haloalkenyl, haloalkynyl) are —CF₃, —CHF₂, —CH₂F,—CF₂CF₃, —CHFCF₃, —CH₂CF₃, —CF₂CH₃, —CHFCH₃, —CF₂CF₂CF₃, —CF₂CH₂CH₃,—CF═CF₂, —CCl═CH₂, —CBr═CH₂, —C≡C—CF₃, —CHFCH₂CH₃, —CHFCH₂CF₃ etc.

From the previously defined haloalkyl (haloalkenyl, haloalkynyl) arealso derived the terms haloalkylene (haloalkenylene, haloalkynylene).Haloalkylene (haloalkenylene, haloalkynylene), unlike haloalkyl(haloalkenyl, haloalkynyl), is bivalent and requires two bindingpartners. Formally, the second valency is formed by removing a hydrogenatom from a haloalkyl (haloalkenyl, haloalkynyl).

Corresponding groups are for example —CH₂F and —CHF—, —CHFCH₂F and—CHFCHF— or >CFCH₂F etc.

The above definitions also apply if the corresponding halogen-containinggroups are part of another (combined) group.

Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.

Cycloalkyl is made up of the subgroups monocyclic hydrocarbon rings,bicyclic hydrocarbon rings and spiro-hydrocarbon rings. The systems aresaturated. In bicyclic hydrocarbon rings two rings are joined togetherso that they have at least two carbon atoms together. Inspiro-hydrocarbon rings one carbon atom (spiroatom) belongs to two ringstogether.

If a cycloalkyl is to be substituted, the substitutions may take placeindependently of one another, in the form of mono- or polysubstitutionsin each case, on all the hydrogen-carrying carbon atoms. Cycloalkylitself may be linked as a substituent to the molecule via every suitableposition of the ring system.

Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl,bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl(octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthyl),bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norcaranyl),bicyclo[3.1.1]heptyl (pinanyl), spiro[2.5]octyl, spiro[3.3]heptyl etc.

The above definition for cycloalkyl also applies if cycloalkyl is partof another (combined) group as for example in C_(x-y)cycloalkylamino,C_(x-y)cycloalkyloxy or C_(x-y)cycloalkylalkyl.

If the free valency of a cycloalkyl is saturated, then an alicyclicgroup is obtained.

The term cycloalkylene can thus be derived from the previously definedcycloalkyl. Cycloalkylene, unlike cycloalkyl, is bivalent and requirestwo binding partners. Formally, the second valency is obtained byremoving a hydrogen atom from a cycloalkyl. Corresponding groups are forexample:

-   -   cyclohexyl and

(cyclohexylene).

The above definition for cycloalkylene also applies if cycloalkylene ispart of another (combined) group as for example inHO—C_(x-y)cycloalkyleneamino or H₂N—C_(x-y)cycloalkyleneoxy.

Cycloalkenyl is also made up of the subgroups monocyclic hydrocarbonrings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. However,the systems are unsaturated, i.e. there is at least one C—C double bondbut no aromatic system. If in a cycloalkyl as hereinbefore defined twohydrogen atoms at adjacent cyclic carbon atoms are formally removed andthe free valencies are saturated to form a second bond, thecorresponding cycloalkenyl is obtained.

If a cycloalkenyl is to be substituted, the substitutions may take placeindependently of one another, in the form of mono- or polysubstitutionsin each case, on all the hydrogen-carrying carbon atoms. Cycloalkenylitself may be linked as a substituent to the molecule via every suitableposition of the ring system.

Examples of cycloalkenyl are cycloprop-1-enyl, cycloprop-2-enyl,cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl,cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl,cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl,cyclobuta-1,3-dienyl, cyclopenta-1,4-dienyl, cyclopenta-1,3-dienyl,cyclopenta-2,4-dienyl, cyclohexa-1,3-dienyl, cyclohexa-1,5-dienyl,cyclohexa-2,4-dienyl, cyclohexa-1,4-dienyl, cyclohexa-2,5-dienyl,bicyclo[2.2.1]hepta-2,5-dienyl (norborna-2,5-dienyl),bicyclo[2.2.1]hept-2-enyl (norbornenyl), spiro[4,5]dec-2-enyl etc.

The above definition for cycloalkenyl also applies when cycloalkenyl ispart of another (combined) group as for example inC_(x-y)cycloalkenylamino, C_(x-y)cycloalkenyloxy orC_(x-y)cycloalkenylalkyl.

If the free valency of a cycloalkenyl is saturated, then an unsaturatedalicyclic group is obtained.

The term cycloalkenylene can thus be derived from the previously definedcycloalkenyl. Cycloalkenylene, unlike cycloalkenyl, is bivalent andrequires two binding partners. Formally, the second valency is obtainedby removing a hydrogen atom from a cycloalkenyl. Corresponding groupsare for example:

cyclopentenyl and

(cyclopentenylene) etc.

The above definition for cycloalkenylene also applies if cycloalkenyleneis part of another (combined) group as for example inHO—C_(x-y)cycloalkenyleneamino or H₂N—C_(x-y)cycloalkenyleneoxy.

Aryl denotes mono-, bi- or tricyclic carbocycles with at least onearomatic carbocycle. Preferably, it denotes a monocyclic group with sixcarbon atoms (phenyl) or a bicyclic group with nine or ten carbon atoms(two six-membered rings or one six-membered ring with a five-memberedring), wherein the second ring may also be aromatic or, however, mayalso be partially saturated.

If an aryl is to be substituted, the substitutions may take placeindependently of one another, in the form of mono- or polysubstitutionsin each case, on all the hydrogen-carrying carbon atoms. Aryl itself maybe linked as a substituent to the molecule via every suitable positionof the ring system.

Examples of aryl are phenyl, naphthyl, indanyl (2,3-dihydroindenyl),indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl(1,2,3,4-tetrahydronaphthyl, tetralinyl), dihydronaphthyl(1,2-dihydronaphthyl), fluorenyl etc.

The above definition of aryl also applies if aryl is part of another(combined) group as for example in arylamino, aryloxy or arylalkyl.

If the free valency of an aryl is saturated, then an aromatic group isobtained.

The term arylene can also be derived from the previously defined aryl.Arylene, unlike aryl, is bivalent and requires two binding partners.Formally, the second valency is formed by removing a hydrogen atom froman aryl. Corresponding groups are for example:

-   -   phenyl and

(o, m, p-phenylene),

-   -   naphthyl and

etc.

The above definition for arylene also applies if arylene is part ofanother (combined) group as for example in HO-aryleneamino orH₂N-aryleneoxy.

Heterocyclyl denotes ring systems, which are derived from the previouslydefined cycloalkyl, cycloalkenyl and aryl by replacing one or more ofthe groups —CH₂— independently of one another in the hydrocarbon ringsby the groups —O—, —S— or —NH— or by replacing one or more of the groups═CH— by the group ═N—, wherein a total of not more than five heteroatomsmay be present, at least one carbon atom must be present between twooxygen atoms and between two sulphur atoms or between an oxygen and asulphur atom and the ring as a whole must have chemical stability.Heteroatoms may optionally be present in all the possible oxidationstages (sulphur→sulphoxide —SO—, sulphone —SO₂—; nitrogen→N-oxide). In aheterocyclyl there is no heteroaromatic ring, i.e. no heteroatom is partof an aromatic system.

A direct result of the derivation from cycloalkyl, cycloalkenyl and arylis that heterocyclyl is made up of the subgroups monocyclic heterorings,bicyclic heterorings, tricyclic heterorings and spiro-heterorings, whichmay be present in saturated or unsaturated form.

By unsaturated is meant that there is at least one double bond in thering system in question, but no heteroaromatic system is formed. Inbicyclic heterorings two rings are linked together so that they have atleast two (hetero)atoms in common. In spiro-heterorings one carbon atom(spiroatom) belongs to two rings together.

If a heterocyclyl is substituted, the substitutions may take placeindependently of one another, in the form of mono- or polysubstitutionsin each case, on all the hydrogen-carrying carbon and/or nitrogen atoms.Heterocyclyl itself may be linked as a substituent to the molecule viaevery suitable position of the ring system.

Examples of heterocyclyl are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl,imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl,1,4-dioxanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl,homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl,thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, 1,3-dioxolanyl,tetrahydropyranyl, tetrahydrothiopyranyl, [1,4]-oxazepanyl,tetrahydrothienyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl,dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl,dihydro-pyrimidinyl, dihydrofuryl, dihydropyranyl,tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide,homothiomorpholinyl-S-oxide, 2,3-dihydroazet, 2H-pyrrolyl, 4H-pyranyl,1,4-dihydropyridinyl, 8-aza-bicyclo[3.2.1]octyl,8-aza-bicyclo[5.1.0]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,8-oxa-3-aza-bicyclo[3.2.1]octyl, 3,8-diaza-bicyclo[3.2.1]octyl,2,5-diaza-bicyclo[2.2.1]heptyl, 1-aza-bicyclo[2.2.2]octyl,3,8-diaza-bicyclo[3.2.1]octyl, 3,9-diaza-bicyclo[4.2.1]nonyl,2,6-diaza-bicyclo[3.2.2]nonyl, 1,4-dioxa-spiro[4.5]decyl,1-oxa-3,8-diaza-spiro[4.5]decyl, 2,6-diaza-spiro[3.3]heptyl,2,7-diaza-spiro[4.4]nonyl, 2,6-diaza-spiro[3.4]octyl,3,9-diaza-spiro[5.5]undecyl, 2,8-diaza-spiro[4,5]decyl etc.

Further examples are the structures illustrated below, which may beattached via each hydrogen-carrying atom (exchanged for hydrogen):

Preferably, heterocyclyls are 4 to 8 membered, monocyclic and have oneor two heteroatoms independently selected from oxygen, nitrogen andsulfur Preferred heterocyclyls are: piperazinyl, piperidinyl,morpholinyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl,tetrahydrofuranyl.

The above definition of heterocyclyl also applies if heterocyclyl ispart of another (combined) group as for example in heterocyclylamino,heterocyclyloxy or heterocyclylalkyl.

If the free valency of a heterocyclyl is saturated, then a heterocyclicgroup is obtained.

The term heterocyclylene is also derived from the previously definedheterocyclyl. Heterocyclylene, unlike heterocyclyl, is bivalent andrequires two binding partners. Formally, the second valency is obtainedby removing a hydrogen atom from a heterocyclyl. Corresponding groupsare for example:

-   -   piperidinyl and

-   -   2,3-dihydro-1H-pyrrolyl and

etc.

The above definition of heterocyclylene also applies if heterocyclyleneis part of another (combined) group as for example inHO-heterocyclyleneamino or H₂N-heterocyclyleneoxy.

Heteroaryl denotes monocyclic heteroaromatic rings or polycyclic ringswith at least one heteroaromatic ring, which compared with thecorresponding aryl or cycloalkyl (cycloalkenyl) contain, instead of oneor more carbon atoms, one or more identical or different heteroatoms,selected independently of one another from among nitrogen, sulphur andoxygen, wherein the resulting group must be chemically stable. Theprerequisite for the presence of heteroaryl is a heteroatom and aheteroaromatic system.

If a heteroaryl is to be substituted, the substitutions may take placeindependently of one another, in the form of mono- or polysubstitutionsin each case, on all the hydrogen-carrying carbon and/or nitrogen atoms.Heteroaryl itself may be linked as a substituent to the molecule viaevery suitable position of the ring system, both carbon and nitrogen.

Examples of heteroaryl are furyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, triazinyl, pyridyl-N-oxide, pyrrolyl-N-oxide,pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide,imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide,thiazolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide,triazolyl-N-oxide, tetrazolyl-N-oxide, indolyl, isoindolyl, benzofuryl,benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl,quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl,indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl,benzoxazolyl, pyridopyridyl, pyrimidopyridyl, purinyl, pteridinyl,benzothiazolyl, imidazopyridyl, imidazothiazolyl, quinolinyl-N-oxide,indolyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N-oxide,quinoxalinyl-N-oxide, phthalazinyl-N-oxide, indolizinyl-N-oxide,indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide etc.

Further examples are the structures illustrated below, which may beattached via each hydrogen-carrying atom (exchanged for hydrogen):

Preferably, heteroaryls are 5-6 membered monocyclic or 9-10 memberedbicyclic, each with 1 to 4 heteroatoms independently selected fromoxygen, nitrogen and sulfur.

The above definition of heteroaryl also applies if heteroaryl is part ofanother (combined) group as for example in heteroarylamino,heteroaryloxy or heteroarylalkyl.

If the free valency of a heteroaryl is saturated, a heteroaromatic groupis obtained.

The term heteroarylene is also derived from the previously definedheteroaryl. Heteroarylene, unlike heteroaryl, is bivalent and requirestwo binding partners. Formally, the second valency is obtained byremoving a hydrogen atom from a heteroaryl. Corresponding groups are forexample:

-   -   pyrrolyl and

etc.

The above definition of heteroarylene also applies if heteroarylene ispart of another (combined) group as for example in HO-heteroaryleneaminoor H₂N-heteroaryleneoxy.

By substituted is meant that a hydrogen atom which is bound directly tothe atom under consideration, is replaced by another atom or anothergroup of atoms (substituent). Depending on the starting conditions(number of hydrogen atoms) mono- or polysubstitution may take place onone atom. Substitution with a particular substituent is only possible ifthe permitted valencies of the substituent and of the atom that is to besubstituted correspond to one another and the substitution leads to astable compound (i.e. to a compound which is not convertedspontaneously, e.g. by rearrangement, cyclisation or elimination).

Bivalent substituents such as ═S, ═NR, ═NOR, ═NNRR, ═NN(R)C(O)NRR, ═N₂or the like, may only be substituents on carbon atoms, wherein thebivalent substituent ═O may also be a substituent on sulphur. Generally,substitution may be carried out by a bivalent substituent only at ringsystems and requires replacement of two geminal hydrogen atoms, i.e.hydrogen atoms that are bound to the same carbon atom that is saturatedprior to the substitution. Substitution by a bivalent substituent istherefore only possible at the group —CH₂— or sulphur atoms (═O only) ofa ring system.

Stereochemistry/Solvates/Hydrates

Unless specifically indicated, throughout the specification and appendedclaims, a given chemical formula or name shall encompass tautomers andall stereo, optical and geometrical isomers (e.g. enantiomers,diastereomers, E/Z isomers, etc.) and racemates thereof as well asmixtures in different proportions of the separate enantiomers, mixturesof diastereomers, or mixtures of any of the foregoing forms where suchisomers and enantiomers exist, as well as salts, includingpharmaceutically acceptable salts thereof and solvates thereof such asfor instance hydrates including solvates of the free compounds orsolvates of a salt of the compound.

Salts:

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgement, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein “pharmaceutically acceptable salts” refers to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like.

For example, such salts include salts from ammonia, L-arginine, betaine,benethamine, benzathine, calcium hydroxide, choline, deanol,diethanolamine(2,2′-iminobis(ethanol)), diethylamine,2-(diethylamino)-ethanol, 2-(dimethylamino)-ethanol, 2-aminoethanol,ethylenediamine, N-ethyl-glucamine, hydrabamine, 1H-imidazole, lysine,magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine,potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide,triethanolamine(2,2′,2″-nitrilotris(ethanol), tromethamine, zinchydroxide, acetic acid, 2,2-dichloro acetic acid, adipic acid, alginicacid, ascorbic acid (L), L-aspartic acid, benzenesulfonic acid, benzoicacid, 2,5-dihydroxybenzoic acid, 4-acetamidobenzoic acid, (+)-camphoricacid, (+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citricacid, cyclamic acid, decanoic acid (capric acid), dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonicacid, ethylenediaminetetraacetic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid,D-glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid,glycerophosphoric acid, glycine, glycolic acid, hexanoic acid (caproicacid), hippuric acid, hydrobromic acid, hydrochloric acid, isobutyricacid, DL-lactic acid, lactobionic acid, lauric acid, maleic acid,(−)-L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid,1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, octanoic acid(caprylic acid), oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid (embonic acid), phosphoric acid, propionic acid,(−)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid.

The salts include acetates, ascorbates, benzenesulfonates, benzoates,besylates, bicarbonates, bitartrates, bromides/hydrobromides,Ca-edetates/edetates, camsylates, carbonates, camphorsulfonate,chlorides/hydrochlorides, chlorotheophyllinate, citrates, edisylates,ethane disulfonates, estolates esylates, fumarates, gluceptates,gluconates, glucuronate, glutamates, glycolates, glycollylarsnilates,hexylresorcinates, hippurate, hydrabamines, hydroxymaleates,hydroxynaphthoates, iodides, isethionates, isothionates, lactates,lactobionates, laurylsulfates, malates, maleates, mandelates,methanesulfonates, mesylates, methylbromides, methylnitrates,methylsulfates, mucates, naphthoate, napsylates, nitrates,octadecanoates, oleates, oxalates, pamoates, pantothenates,phenylacetates, phosphates/diphosphates, polygalacturonates,propionates, salicylates, stearates subacetates, succinates, sulfamides,sulfates, sulfosalicylates, tannates, tartrates, teoclates,toluenesulfonates, triethiodides, trifluoroacetates, ammonium,benzathines, chloroprocaines, cholines, diethanolamines,ethylenediamines, meglumines and procaines.

Further pharmaceutically acceptable salts can be formed with cationsfrom metals like aluminium, calcium, lithium, magnesium, potassium,sodium, zinc and the like (also see Pharmaceutical salts, Berge, S. M.et al., J. Pharm. Sci., (1977), 66, 1-19).

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base form of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoro acetate salts), also comprise a part of the invention.

In a representation such as for example

the letter A has the function of a ring designation in order to make iteasier, for example, to indicate the attachment of the ring in questionto other rings.

For bivalent groups in which it is crucial to determine which adjacentgroups they bind and with which valency, the corresponding bindingpartners are indicated in brackets where necessary for clarificationpurposes, as in the following representations:

or (R²)—C(O)NH— or (R²)—NHC(O)—;

Groups or substituents are frequently selected from among a number ofalternative groups/substituents with a corresponding group designation(e.g. R^(a), R^(b) etc). If such a group is used repeatedly to define acompound according to the invention in different parts of the molecule,it is pointed out that the various uses are to be regarded as totallyindependent of one another.

By a therapeutically effective amount for the purposes of this inventionis meant a quantity of substance that is capable of obviating symptomsof illness or of preventing or alleviating these symptoms, or whichprolong the survival of a treated patient.

List of abbreviations Ac acetyl AcCN acetonitrile aq. aquatic, aqueousATP adenosine triphosphate Bn benzyl Boc tert-butyloxycarbonyl Bu butylc concentration d day(s) dba dibenzylideneacetone TLC thin layerchromatography Davephos2-dimethylamino-2′-dicyclohexylaminophosphinobiphenyl DBAdibenzylideneacetone DCM dichloromethane DEA diethylamine DEAD diethylazodicarboxylate DIPEA N-ethyl-N,N-diisopropylamine (Hünig's base) DMAP4-N,N-dimethylaminopyridine DME 1,2-dimethoxyethane DMFN,N-dimethylformamide DMSO dimethylsulphoxide DPPAdiphenylphosphorylazide dppf 1,1′-bis(diphenylphosphino)ferrocene EDTAethylenediaminetetraacetic acid EGTA ethyleneglycoltetraacetic acid eqequivalent(s) ESI electron spray ionization Et ethyl Et₂O diethyl etherEtOAc ethyl acetate EtOH ethanol h hour HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate HPLC high performance liquid chromatography IBX2-iodoxy benzoic acid i iso conc. concentrated LC liquid chromatographyLiHMDS lithium bis(trimethylsilyl)amide sln. solution Me methyl MeOHmethanol min minutes MPLC medium pressure liquid chromatography MS massspectrometry MTBE methyl tert-butyl ether NBS N-bromo-succinimide NISN-iodo-succinimide NMM N-methylmorpholine NMP N-methylpyrrolidone NPnormal phase n.a. not available PBS phosphate-buffered saline Ph phenylPr propyl Py pyridine rac racemic red. reduction Rf (R_(f)) retentionfactor RP reversed phase rt ambient temperature SFC supercritical fluidchromatography S_(N) nucleophilic substitution TBAF tetrabutylammoniumfluoride TBDMS tert-butyldimethylsilyl TBME tert-butylmethylether TBTUO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium tetrafluoroboratetBu tert-butyl TEA triethylamine temp. temperature tert tertiary Tftriflate TFA trifluoroacetic acid THF tetrahydrofuran TMS trimethylsilylt_(Ret.) retention time (HPLC) TRIS tris(hydroxymethyl)-aminomethaneTsOH p-toluenesulphonic acid UV ultraviolet

Features and advantages of the present invention will become apparentfrom the following detailed examples which illustrate the principles ofthe invention by way of example without restricting its scope:

Preparation of the Compounds According to the Invention

General

Unless stated otherwise, all the reactions are carried out incommercially obtainable apparatus using methods that are commonly usedin chemical laboratories. Starting materials that are sensitive to airand/or moisture are stored under protective gas and correspondingreactions and manipulations therewith are carried out under protectivegas (nitrogen or argon).

The compounds according to the invention are named in accordance withCAS rules using the software Autonom (Beilstein). If a compound is to berepresented both by a structural formula and by its nomenclature, in theevent of a conflict the structural formula is decisive.

Microwave reactions are carried out in an initiator/reactor made byBiotage or in an Explorer made by CEM or in Synthos 3000 or Monowave3000 made by Anton Paar in sealed containers (preferably 2, 5 or 20 mL),preferably with stirring.

Chromatography

The thin layer chromatography is carried out on ready-made silica gel 60TLC plates on glass (with fluorescence indicator F-254) made by Merck.

The preparative high pressure chromatography (RP HPLC) of the examplecompounds according to the invention is carried out on Agilent or Gilsonsystems with columns made by Waters (names: SunFire™ Prep C18, OBD™ 10μm, 50×150 mm or SunFire™ Prep C18 OBD™ 5 μm, 30×50 mm or XBridge™ PrepC18, OBD™ 10 μm, 50×150 mm or XBridge™ Prep C18, OBD™ 5 μm, 30×150 mm orXBridge™ Prep C18, OBD™ 5 μm, 30×50 mm) and YMC (names: Actus-TriartPrep C18, 5 μm, 30×50 mm).

Different gradients of H₂O/acetonitrile are used to elute the compounds,while for Agilent systems 5% acidic modifier (20 mL HCOOH to 1 LH₂O/acetonitrile (1/1)) is added to the water (acidic conditions). ForGilson systems the water is added 0.1% HCOOH.

For the chromatography under basic conditions for Agilent systemsH₂O/acetonitrile gradients are used as well, while the water is madealkaline by addition of 5% basic modifier (50 g NH₄HCO₃+50 mL NH₃ (25%in H₂O) to 1 L with H₂O). For Gilson systems the water is made alkalineas follows: 5 mL NH₄HCO₃ solution (158 g in 1 L H₂O) and 2 mL NH₃ (28%in H₂O) are replenished to 1 L with H₂O.

The supercritical fluid chromatography (SFC) of the intermediates andexample compounds according to the invention is carried out on a JASCOSFC-system with the following columns: Chiralcel OJ (250×20 mm, 5 μm),Chiralpak AD (250×20 mm, 5 μm), Chiralpak AS (250×20 mm, 5 μm),Chiralpak IC (250×20 mm, 5 μm), Chiralpak IA (250×20 mm, 5 μm),Chiralcel OJ (250×20 mm, 5 μm), Chiralcel OD (250×20 mm, 5 μm),Phenomenex Lux C2 (250×20 mm, 5 μm).

The analytical HPLC (reaction control) of intermediate and finalcompounds is carried out using columns made by Waters (names: XBridge™C18, 2.5 μm, 2.1×20 mm or XBridge™ C18, 2.5 μm, 2.1×30 mm) and YMC(names: Triart C18, 3.0 μm, 2.0×30 mm). The analytical equipment is alsoequipped with a mass detector in each case.

HPLC-Mass Spectroscopy/UV-Spectrometry

The retention times/MS-ESI⁺ for characterizing the example compoundsaccording to the invention are produced using an HPLC-MS apparatus (highperformance liquid chromatography with mass detector). Compounds thatelute at the injection peak are given the retention time t_(Ret.)=0.00.

HPLC-Methods

Method A

HPLC Agilent 1100 Series MS Agilent LC/MSD SL column Waters, Xbridge ™C18, 2.5 μm, 2.1 × 20 mm, Part. No. 186003201 solvent A: 20 mMNH₄HCO₃/NH₃ pH 9 B: acetonitrile (HPLC grade) detection MS: positive andnegative mass range: 120-900 m/z fragmentor: 120 gain EMV: 1 threshold:150 stepsize: 0.2 UV: 315 nm bandwidth: 170 nm reference: off range:230-400 nm range step: 1.00 nm peakwidth: <0.01 min slit: 1 nm injection5 μL flow 1.00 mL/min column temperature 60° C. gradient     0.00 min10% B 0.00-1.50 min 10% → 95% B 1.50-2.00 min 95% B 2.00-2.10 min 95% →10% BMethod B

HPLC Agilent 1200 Series MS Agilent 6130 Quadropole LC/MS column Waters,Xbridge ™ C18, 2.5 μm, 2.1 × 30 mm solvent A: 20 mM NH₄HCO₃/NH₃ inwater; pH 9.3 B: acetonitrile (HPLC grade) detection MS: polarity:positive ionizator: MM-ES + APCI mass range: 150-750 m/z fragmentorvalues: mass fragmentor 150  70 750 110 gain EMV: 1.00 threshold: 150stepsize: 0.2 UV: 254 nm: reference off 214 nm: reference off range:190-400 nm range step: 2.00 nm threshold: 1.00 mAU peakwidth: 0.0025 min(0.05 s) slit: 4 nm injection 0.5 μL flow 1.400 mL/min columntemperature 45° C. gradient 0.00-1.00 min 15% -> 95% B 1.00-1.30 min 95%BMethod C

HPLC Agilent 1200 Series MS Agilent 6130 Quadropole LC/MS column YMC,Triart C18, 3.0 μm, 2.0 × 30 mm, 12 nm solvent A: water + 0.1% HCOOH B:acetonitrile + 0.1% HCOOH (HPLC grade) detection MS: polarity: positivemass range: 150-750 m/z fragmentor values: mass fragmentor 150  70 750110 gain EMV: 1.00 threshold: 150 stepsize: 0.20 UV: 254 nm: referenceoff 214 nm: reference off range: 190-400 nm range step: 4.00 nmthreshold: 1.00 mAU peakwidth: 0.005 min (0.1 s) slit: 4 nm injection0.5 μL flow 1.400 mL/min column temperature 45° C. gradient 0.00-1.00min  15% → 100% B 1.00-1.13 min 100% BMethod D

HPLC Agilent 1200 Series MS Agilent 6130 Quadropole LC/MS column Waters,Xbridge ™ C18, 2.5 μm, 2.1 × 30 mm solvent A: 20 mM NH₄HCO₃/NH₃ inwater; pH 9.3 B: acetonitrile (HPLC grade) detection MS: polarity:positive + negative ionization: MM-ES mass range: 150-750 m/z fragmentorvalues: mass fragmentor 150  70 750 110 gain EMV: 1.00 threshold: 150stepsize: 0.2 UV: 254 nm: reference off 214 nm: reference off range:190-400 nm range step: 2.00 nm threshold: 1.00 mAU peakwidth: 0.0025 min(0.05 s) slit: 4 nm injection 0.5 μL flow 1.400 mL/min columntemperature 45° C. gradient 0.00-1.00 min 15% → 95% B 1.00-1.30 min 95%BMethod E

HPLC Agilent 1200 Series: MS Agilent 6130 Quadropole LC/MS columnWaters, Xbridge ™ C18, 2.5 μm, 2.1 × 30 mm Column XP; Part. No.186006028 solvent A: 20 mM NH₄HCO₃/NH₃ in water; pH 9.3 B: acetonitrile(HPLC grade) detection MS: polarity: positive + negative ionizator:API-ES mass range: 150-750 m/z fragmentor values: mass fragmentor 150 70 750 110 gain EMV: 1.00 threshold: 150 stepsize: 0.2 UV: 254 nm:reference off 214 nm: reference off range: 190-400 nm range step: 2.00nm threshold: 1.00 mAU peakwidth: 0.0025 min (0.05 s) slit: 4 nminjection 0.5 μL flow 1.400 mL/min column temperature 45° C. gradient0.00-1.00 min 15% → 95% B 1.00-1.30 min 95% BMethod F

HPLC Agilent 1200 Series MS Agilent 6130 Quadropole LC/MS column YMC,Triart C18, 3.0 μm, 2.0 × 30 mm, 12 nm solvent A: water + 0.1% HCOOH B:acetonitrile + 0.1% HCOOH (HPLC grade) detection MS: polarity:positive + negative mass range: 150-750 m/z fragmentor values: massfragmentor 150  70 750 110 gain EMV: 1.00 threshold: 150 stepsize: 0.20UV: 254 nm: reference off 214 nm: reference off range: 190-400 nm rangestep: 4.00 nm threshold: 1.00 mAU peakwidth: 0.0063 min (0.13 s) slit: 4nm injection 0.5 μL flow 1.400 mL/min column temperature 45° C. gradient0.00-1.00 min  15% → 100% B 1.00-1.13 min 100% BMethod G

HPLC Agilent 1200 Series MS Agilent 6130 Quadropole LC/MS column YMC,Triart C18, 3.0 μm, 2.0 × 30 mm, 12 nm solvent A: water + 0.1% HCOOH B:acetonitrile + 0.1% HCOOH (HPLC grade) detection MS: polarity:positive + negative mass range: 150-750 m/z fragmentor values: MassFragmentor 150  70 750 110 gain EMV: 1.00 threshold: 150 stepsize: 0.20UV: 254 nm: reference off 230 nm: reference off 214 nm: reference offrange: 190-400 nm range step: 4.00 nm threshold: 1.00 mAU peakwidth:0.005 min (0.1 s) slit: 4 nm injection 0.5 μL flow 1.400 mL/min columntemperature 45° C. gradient 0.00-1.00 min  15% → 100% B 1.00-1.13 min100% BMethod H

HPLC Agilent 1200 Series MS Agilent 6130 Quadropole LC/MS column YMC,Triart C18, 3.0 μm, 2.0 × 30 mm, 12 nm solvent A: water + 0.1% HCOOH B:acetonitrile + 0.1% HCOOH (HPLC grade) detection MS: polarity:positive + negative mass range: 200-800 m/z fragmentor: 70 gain: 1.00threshold: 150 stepsize: 0.20 UV: 254 nm: reference off 230 nm:reference off range: 190-400 nm range step: 2.00 nm peakwidth: >0.01 min(0.2 s) slit: 4 nm injection 1.0 μL flow 1.000 mL/min column temperature45° C. gradient 0.00-0.10 min  5% B 0.10-1.85 min  5% B → 95.0% B1.85-1.90 min 95% B 1.95-1.92 min 95% B → 5.0% BMethod I

HPLC Agilent 1200 Series MS Agilent 6130 Quadropole LC/MS column YMC,Triart C18, 3.0 μm, 2.0 × 30 mm, 12 nm solvent A: water + 0.1% HCOOH B:acetonitrile + 0.1% HCOOH (HPLC grade) detection MS: polarity:positive + negative mass range: 200-800 m/z fragmentor: 70 gain: 1.00threshold: 150 stepsize: 0.20 UV: 254 nm: reference off 230 nm:reference off range: 190-400 nm range step: 2.00 nm peakwidth: >0.01 min(0.2 s) slit: 4 nm injection 1.0 μL flow 1.000 mL/min column temperature45° C. gradient 0.00-0.10 min 15% B 0.10-1.55 min 15% B → 95.0% B1.55-1.90 min 95% B 1.95-1.92 min 95% B → 15.0% B

The compounds according to the invention are prepared by the methods ofsynthesis described hereinafter in which the substituents of the generalformulae have the meanings given hereinbefore. These methods areintended as an illustration of the invention without restricting itssubject matter and the scope of the compounds claimed to these examples.Where the preparation of starting compounds is not described, they arecommercially obtainable or may be prepared analogously to known priorart compounds or methods described herein. Substances described in theliterature are prepared according to the published methods of synthesis.

General Reaction Scheme and Summary of the Synthesis Route

Novel compounds of structure (I) can be prepared stepwise by a synthesisroute starting from protected amino acids A-1. First, an acylationreaction using acrylic acid derivatives A-2 yields compounds ofstructure A-3 (method A). Acrylic acids which are not directly availablecan be obtained e.g. by WITTIG reaction (B-1, B-2, not depicted inscheme 1). Treatment of intermediates A-3 under acidic conditions,preferentially with trifluoro acetic acid (for PG=tBu/Boc), forms freeunsaturated amino acid derivatives A-4 (method B). A decarboxylative1,3-dipolar cycloaddition of A-4 and isatin derivatives A-5 yieldscycloadducts A-6 as a mixture of diastereo isomers and builds up thespiro system (method C). The diastereomers can be separated, e.g. byHPLC or SFC. The obtainable racemic mixture can be resolved by chiralSFC separation or at any later stage in the synthesis. Also all othermeans known for separation of enantiomers can be applied here or afterany later synthetic step herein described, e.g. crystallisation, chiralresolution, chiral HPLC etc. (see also Enantiomers, racemates, andresolutions, Jean Jacques, Andre Collet, Samuel H Wilen John Wiley andSons, N Y, 1981).

In case of U≠NH, A-6 can be reacted with aldehydes or ketones in areductive amination reaction to give compounds of structure (I)(introduction of R¹, method D). Alternatively, an alkylation, addition,acylation or sulfonylation reaction can be performed with A-6 toadditional compounds of formula (I).

In case of U=NH, A-6 can also be reacted with aldehydes or ketones in areductive amination reaction or can by acylated or sulfonylated(introduction of R¹, method D). Compounds thus obtained can be modifiedin an additional BUCHWALD reaction (introduction of R⁵, method E1 andE2) to give additional compounds (I).

Compounds (I) which are initially obtained can be derivatized inoptional derivatization steps not explicitly depicted in the schemes inall residues, especially in R⁵ (for U=NH or U=NR⁵), if they carryfunctional groups, that can be further modified such as e.g. halogenatoms, amino and hydroxy groups (including cyclic amines), carboxylicacid or ester functions, nitriles etc. to further compounds (I) by wellestablished organic chemical transformations such as metal-catalyzedcross coupling reactions, acylation, amidation, addition, reduction or(reductive) alkylation or cleavage of protecting groups. Theseadditional steps are not depicted in the general schemes. Likewise, itis also possible to include these additional steps in the syntheticroutes depicted in the general schemes, i.e. to carry out derivatizationreactions with intermediate compounds. In addition, it may also bepossible that building blocks bearing protecting groups are used, i.e.further steps for deprotection are necessary.

Compounds (I) have been tested for their activity to affect MDM2-p53interaction in their racemic form or alternatively as the enantiopureform. Each of the two enantiomers of a racemic mixture may have activityagainst MDM2 although with a different binding mode. Enantiopurecompounds are marked with the label “Chiral”. Compounds listed in anytable below that are labeled “Chiral” (both intermediates as well ascompounds (I) according to the invention) can be separated by SFCchromatography from their enantiomer or are synthesized from enantiopurestarting material which is separated by SFC.

Example:

Structure A defines the racemic mixture of compounds with structure Band C, i.e. structure A encompasses two structures (compounds B and C),whereas structures B and C, respectively, are enantiopure and onlydefine one specific compound. Thus, formulae (I) and (Ia)

with a set of specific definitions for groups R¹ to R³, R⁷, U, V, W, X,Y, n and q represent the racemic mixture of two enantiomers (→(I);structure A above is one specific example of such a racemic mixture) ora single enantiomer (→(Ia); structure B above is one specificenantiomer). The same definition applies to synthetic intermediates.Synthesis of Intermediates A-1Experimental Procedure for the Synthesis of A-1a

To a solution of 4-formyl-benzoic acid methyl ester (2.8 g, 17.5 mmol)in DCM is added 4-amino-2-tert-butoxycarbonylamino-butyric acidtert-butyl ester A-1a (1.00 g, 3.6 mmol) and AcOH (4.1 mL, 73.0 mmol).The reaction mixture is stirred at rt for 30 min before NaBH(OAc)₃ (6.2g, 29 mmol) is added. The reaction is allowed to stir over night untilHPLC/MS analysis indicates complete consumption of the startingmaterial. The reaction is quenched by the addition of sat. aq. NaHCO₃solution and the resulting biphasic mixture is extracted with DCM. Thecombined organic fractions are dried with MgSO₄, filtered and thesolvents are removed under reduced pressure. The crude material is usedwithout further purification.

The following intermediates A-1 (table 1) are available in an analogousmanner.

TABLE 1 # structure t_(ret) [min] [M + H]⁺ HPLC method A-1b

1.56 [M—Boc] 345 A A-1c

1.56 [M—Boc] 345 A A-1d

0.49 409 F A-1e

0.49 409 FSynthesis of Intermediates A-2Experimental Procedure for the Synthesis of A-2a

2-Chloro-3-fluoro-pyridine-4-carbaldehyde (1 g, 6.3 mmol) is dissolvedin anhydrous MTBE (10 mL) under an argon atmosphere. Methyl(triphenylphosphoranylidene)acetate (2.1 g, 6.3 mmol) is added in oneportion and the reaction mixture is stirred at rt for 1 h. Water andEtOAc is added and the phases are separated. The organic phase is driedwith MgSO₄, filtered and the solvent is removed under reduced pressure.The residue is purified by reversed phase column chromatography givingpure (E)-3-(2-chloro-3-fluoro-pyridin-4-yl)-acrylic acid methyl esterB-2a.

B-2a (780 mg, 3.6 mmol) is dissolved in THF (3 mL) and 2 M NaOH is added(3.6 mL, 7.2 mmol). The reaction mixture is stirred at 60° C. for 1 hbefore it is quenched by the addition of 2 M HCl. Extraction with EtOAcand subsequent drying of the organic phase using MgSO₄ yields crude A-2aupon removal of the solvents under reduced pressure. Reversed phasecolumn chromatography gives pure(E)-3-(2-chloro-3-fluoro-pyridin-4-yl)-acrylic acid A-2a.

Further building blocks A-2 are available in an analogous mannerstarting from different carbaldehydes B-1.

TABLE 2 HPLC # structure t_(ret) [min] [M + H]⁺ method A-2a

0.0 202 ASynthesis of Intermediates A-3 (Method A)Experimental Procedure for the Synthesis of A-3a

3-Chloro-2-fluoro cinnamic acid A-2b (10.3 g, 50.67 mmol) is suspendedin anhydrous DMF (300 mL) at 0° C. and DIPEA (19.5 mL, 120.65 mmol) andHATU (20.39 g, 53.09 mmol) are added to the reaction mixture. Thereaction mixture is stirred at 0° C. for 30 min. A solution of(S)-4-amino-2-tert-butoxycarbonylamino-butyric acid tert-butyl esterhydrochloride A-1a (15.0 g, 48.26 mmol) in DMF (100 mL) is addeddropwise over a period of 15 min. The reaction mixture is stirred foradditional 60 min and sat. aq. NH₄Cl solution is added. Deionized wateris added and the mixture is extracted with a 1:1 mixture of EtOAc andcyclohexane. The layers are separated and the organic phase is washedwith deionized water and dried with MgSO₄. The solvents are removedunder reduced pressure and(S)-2-tert-butoxycarbonylamino-4-[(E)-3-(3-chloro-2-fluoro-phenyl)-acryloylamino]-butyricacid tert-butyl ester A-3a is used without further purification.

The following intermediates A-3 (table 3) are available in an analogousmanner starting from different acrylic acids A-2 and protected aminoacids A-1.

TABLE 3 # structure t_(ret) [min] [M + H]⁺ HPLC method A-3a

1.56 [M + H—Boc]⁺ 357 A A-3b

1.56 [M + H—Boc]⁺ 357 A A-3c

1.45 [M + H—Boc]⁺ 483 H A-3d

1.45 [M + H—Boc]⁺ 483 H A-3e

0.82 443 G A-3f

0.82 443 G A-3g

n.a. n.a. A-3h

n.a. n.a. A-3j

1.44 466 A A-3k

1.44 466 A A-3l

0.57 n.a. G A-3m

0.57 n.a. G A-3n

0.94 [M + H—Boc]⁺ 505 F A-3o

0.94 [M + H—Boc]⁺ 505 F A-3p

0.99 n.a. F A-3q

0.99 n.a. FSynthesis of intermediates A-4 (method B)Experimental procedure for the synthesis of A-4a

(S)-2-tert-Butoxycarbonylamino-4-[(E)-3-(3-chloro-2-fluoro-phenyl)-acryloylamino]-butyricacid tert-butyl ester A-3a (22.4 g, 48.9 mmol) is dissolved in DCM (150mL). TFA (35 mL) is added at 0° C. and the reaction mixture is slowlywarmed to rt. The reaction mixture is heated to reflux for 24 h. Beforeit is concentrated in vacuo, aq. NaOH (4 M) is added at 0° C. until a pHof 12 is reached. Addition of aq. HCl (2 M) results in the formation ofa precipitate at pH 6-7 which is filtered off. The solid residue(S)-2-amino-4-[(E)-3-(3-chloro-2-fluoro-phenyl)-acryloylamino]-butyricacid hydrochloride A-4a is washed with water and acetonitrile and driedat 50° C. under reduced pressure.

The following intermediates A-4 (Table 4) are available in an analogousmanner starting from different intermediates A-3.

TABLE 4 # structure t_(ret) [min] [M + H]⁺ HPLC method A-4a

0.91 301 A A-4b

0.91 301 A A-4c

0.32 283 G A-4d

0.32 283 G A-4e

0.63 −287 A A-4f

0.63 −287 A A-4g

0.21 288 A A-4h

0.21 288 A A-4i

0.38 302 G A-4j

0.38 302 G A-4k

1.13 449 A A-4l

1.13 449 A A-4m

1.07 435 A A-4n

1.07 435 ASynthesis of Intermediate A-5Experimental Procedure for the Synthesis of A-5b

3,3-Dibromo-6-chloro-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (7.6 g,23.3 mmol) is suspended in acetonitrile (500 mL) and water (25 mL).AgNO₃ (8.9 g, 52.7 mmol) is added and the reaction mixture is stirred atrt for 1 h. Acetonitrile is removed under reduced pressure and EtOAc isadded. The phases are separated and the organic layer is dried withMgSO₄. Removal of the solvents gives pure6-chloro-1H-pyrrolo[2,3-b]pyridine-2,3-dione A-5b.

Synthesis of Intermediate A-6 (Method C)

Experimental Procedure for the Synthesis of A-6a and A-6c

(S)-2-Amino-4-[(E)-3-(3-chloro-2-fluoro-phenyl)-acryloylamino]-butyricacid A-4a (0.34 g, 1.13 mmol), 6-chloro-1H-indole-2,3-dione A-5a (2.1 g,1.13 mmol) and ground, activated 4 Å molecular sieves are suspended inanhydrous MeOH (15 mL) in a microwave vial. The reaction vessel issealed with Teflon caps and irradiated for 30 min at a final temperatureof 100° C. After cooling to rt, the crude mixture is filtered over a padof Celite® and solvents are removed under reduced pressure. The crudereaction mixture is purified by reversed phase HPLC which givesdiastereomers A-6a and A-6c.

The following intermediates A-6 (Table 5) are available in an analogousmanner starting from different intermediates A-4 and A-5.

TABLE 5 # structure t_(ret) [min] [M + H]⁺ HPLC method A-6a

0.49 420 G A-6b

0.49 420 G A-6c

0.45 420 G A-6d

0.53 438 G A-6e

0.53 438 G A-6f

0.50 451 G A-6g

0.50 451 G A-6h

0.53 512 G A-6i

0.53 512 G A-6j

n.a. n.a. A-6k

n.a. n.a. A-6l

0.99 402 A A-6m

0.99 402 A A-6n

1.25 498 A A-6o

1.25 498 A A-6p

0.93 421 A A-6q

0.93 421 A A-6r

0.89 421 A A-6s

0.99 406 A A-6t

0.99 406 A A-6u

0.99 406 A A-6v

1.30 421 A A-6w

1.30 421 A A-6x

1.22 421 A A-6y

0.89 421 A A-6z

0.89 421 A A-6aa

0.93 421 A A-6ab

0.50 451 G A-6ac

0.50 451 G A-6ad

0.89 407 A A-6ae

0.89 407 A A-6af

1.44 568 A A-6ag

1.37 568 A A-6ah

1.37 568 A A-6ai

1.42 554 A A-6aj

1.42 554 A A-6ak

1.39 554 ASynthesis of Compounds (I) According to the Invention (Method D)Experimental Procedure for the Synthesis of Compound I-1

A-6a (0.54 g, 1.27 mmol), AcOH (0.23 g, 3.8 mmol), andcyclopropanecarboxaldehyde (0.48 mL, 6.37 mmol) are dissolved inanhydrous DMF (1 mL) and sodium triacetoxyborohydride (0.54 g, 2.55mmol) is added. The reaction mixture is stirred at rt for 15 h beforedeionized water is added. EtOAc is added and the phases are separated.After washing with water, the organic phase is dried with MgSO₄ and thesolvents are removed under reduced pressure. If needed the product ispurified using reversed phase HPLC resulting in purified I-1.

The following compounds (I) (table 6) are available in an analogousmanner starting from different intermediates A-6.

TABLE 6 # structure t_(ret) [min] [M + H]⁺ HPLC method I-1

1.29 474 A I-2

1.29 474 A I-3

1.28 456 A I-4

1.28 456 A I-5

1.38 554 A I-6

1.38 554 A I-7

1.35 536 A I-8

1.35 536 A I-9

1.28 555 A I-10

1.28 555 A I-11

1.37 552 A I-12

1.37 552 A I-13

1.36 488 A I-14

1.36 488 A I-15

1.41 490 A I-16

1.41 490 A I-17

1.30 492 A I-18

1.30 492 A I-19

1.50 488 A I-20

1.50 488 A I-21

1.31 518 A I-22

1.31 518 A I-23

1.40 454 A I-24

1.40 454 A I-25

1.47 566 A I-26

1.47 566 A I-27

1.28 555 A I-28

1.28 555 A I-29

0.93 622 F I-30

0.93 622 F I-31

1.00 638 F I-32

1.00 638 F I-33

0.93 688 F I-34

0.93 688 F I-35

0.92 702 F I-36

0.92 702 F I-37

1.39 475 A I-38

1.39 475 A I-39

1.24 460 A I-40

1.23 460 A I-41

1.21 504 A I-42

1.21 504 A I-43

1.47 540 A I-44

1.47 540 A I-45

0.58 464 G I-46

0.58 464 G I-47

0.75 476 G I-48

0.75 476 G I-49

0.69 500 A I-50

0.69 500 A I-51

0.68 510 A I-52

0.68 510 A I-53

1.25 541 A I-54

1.25 541 A I-55

0.61 461 G I-56

0.61 461 G I-57

0.90 608 C I-58

0.90 608 C I-59

1.14 674 A I-60

1.14 674 A I-61

1.16 674 A I-62

1.16 674 ASynthesis of Further Compounds (I) by BUCHWALD Reaction with InitiallyObtained Compounds (I) (Method E1)Experimental Procedure for the Synthesis of I-63

I-1 (50 mg, 0.11 mmol), 4-bromo-benzoic acid methyl ester (34 mg, 0.16mmol), cesium carbonate (51 mg, 0.16 mmol), Xantphos (6.1 mg, 0.01mmol), and palladium dibenzylidene acetone (Pd₂dba₃; 9.6 mg, 0.01 mmol)are suspended in 1,4-dioxane (1 mL) in a microwave vial. The reactionmixture is sealed and stirred at 120° C. for 16 h. The reaction mixtureis diluted with acetonitrile, filtered through a syringe filter, thesolvents are removed under reduced pressure and the crude material ispurified by reversed phase HPLC yielding I-63.

The following compounds (I) (table 7) are available in an analogousmanner starting from initially obtained compounds (I).

TABLE 7 # structure t_(ret) [min] [M + H]⁺ HPLC method I-63

1.54 608 A I-64

1.54 608 A I-65

1.63 652 A I-66

1.63 652 A I-67

0.88 653 G I-68

0.88 653 G I-69

1.70 622 A I-70

1.70 622 A I-71

1.61 688 A I-72

1.24 618 A I-73

1.24 618 A I-74

1.39 644 A I-75

1.39 644 A I-76

1.41 628 A I-77

1.41 628 A I-78

1.58 642 A I-79

1.58 642 A I-80

1.52 643 A I-81

1.52 643 A I-82

1.72 652 A I-83

1.72 652 A I-84

1.74 640 A I-85

1.74 640 A I-86

1.50 575 A I-87

1.50 575 A I-88

0.88 595 G I-89

0.88 595 G I-90

1.41 595 A I-91

1.41 595 A I-92

1.50 551 A I-93

1.50 551 A I-94

0.88 626 G I-95

0.88 626 G I-96

0.96 622 D I-97

0.96 622 D I-98

0.89 590 G I-99

0.89 590 G I-100

1.58 652 A I-101

1.58 652 A I-102

0.70 606 G I-103

0.70 606 G I-104

0.70 595 G I-105

0.70 595 G I-106

1.54 608 A I-107

1.54 608 A I-108

0.92 688 G I-109

0.92 688 G I-110

0.91 733 G I-111

0.91 733 G I-112

1.61 688 A I-113

1.74 622 A I-114

1.74 622 A I-115

1.63 652 A I-116

1.63 652 A I-117

0.95 624 D I-118

0.95 624 D I-119

0.91 653 G I-120

0.91 653 G I-121

0.91 636 G I-122

0.91 636 G I-123

1.66 594 A I-124

1.66 594 A I-125

1.62 624 A I-126

1.62 624 A I-127

0.81 594 G I-128

0.81 594 G I-129

0.83 598 G I-130

0.83 598 G I-131

0.88 636 G I-132

0.88 636 G I-133

0.94 610 G I-134

0.94 610 G I-135

0.88 644 G I-136

0.88 644 G I-137

0.93 636 G I-138

0.93 636 G I-139

0.84 601 G I-140

0.84 601 G I-141

0.91 594 D I-142

0.52 580 D I-143

1.01 636 G I-144

1.66 622 A I-145

0.95 608 G I-146

0.95 674 D I-147

0.95 674 D I-148

1.56 689 A I-149

1.56 689 A I-150

0.86 595 G I-151

0.86 595 GSynthesis of Further Compounds (I) by BUCHWALD Reaction with InitiallyObtained Compounds (I) (Method E2)Experimental Procedure for the Synthesis of I-152

I-41 (35 mg, 0.07 mmol), 4-bromo-2-methoxy-benzoic acid methyl ester(22.1 mg, 0.09 mmol), cesium carbonate (33.9 mg, 0.10 mmol), Xantphos(8.0 mg, 0.01 mmol), and palladium trifluoroacetate (Pd(TFA)₂; 2.3 mg,0.007 mmol) are suspended in 1,4-dioxane (1 mL) in a microwave vial. Thereaction is sealed and irradiated in a synthesis microwave (BiotageInitiator) at 120° C. for 1 h. After consumption of the startingmaterial, the reaction is diluted with acetonitrile and filtered througha syringe filter. The solvents are removed under reduced pressureyielding I-152.

The following compounds (I) (table 8) are available in an analogousmanner starting from initially obtained compounds (I).

TABLE 8 # structure t_(ret) [min] [M + H]⁺ HPLC method I-152

0.87 669 G I-153

0.87 669 G I-154

0.91 639 G I-155

0.91 639 G I-156

0.91 657 G I-157

0.91 657 G I-158

0.95 677 G I-159

0.95 677 G I-160

0.53 624 B I-161

1.00 392 G I-162

1.00 392 G I-163

0.84 636 G I-164

0.84 636 G I-165

0.91 599 G I-166

0.91 599 G I-167

0.97 622 G I-168

0.93 602 G I-169

0.93 602 GSynthesis of Further Compounds (I) by Alkaline Ester Saponification ofInitially Obtained Compounds (I)Experimental Procedure for the Synthesis of I-167

I-63 (22 mg, 0.04 mmol) is dissolved in MeOH (1 mL) and aqueous NaOHsolution (0.5 mL, 4 M) is added. The reaction mixture is heated toreflux for 1 h. After acidification with aqueous HCl (2 M) andextraction with EtOAc the organic phase is dried with MgSO₄ andfiltered. Purification with reversed phase HPLC yields I-167.

The following compounds (I) (table 9) are available in an analogousmanner starting from initially obtained compounds (I).

TABLE 9 # structure t_(ret) [min] [M + H]⁺ HPLC method I-170

1.07 594 A I-171

1.07 594 A I-172

1.07 594 A I-173

1.07 612 A I-174

1.07 612 A I-175

1.05 594 A I-176

1.05 594 A I-177

1.06 576 A I-178

1.06 576 A I-179

1.09 624 A I-180

1.09 624 A I-181

1.06 606 A I-182

1.06 606 A I-183

1.04 595 A I-184

1.04 595 A I-185

1.14 674 A I-186

1.15 674 A I-187

0.81 674 G I-188

1.16 719 A I-189

1.16 719 A I-190

1.28 626 A I-191

1.28 626 A I-192

1.05 639 A I-193

1.05 639 A I-194

1.27 638 A I-195

1.27 638 A I-196

1.26 608 A I-197

1.26 608 A I-198

1.12 608 A I-199

1.12 608 A I-200

1.13 638 A I-201

1.13 638 A I-202

1.14 610 A I-203

1.09 610 A I-204

1.14 640 A I-205

1.14 640 A I-206

1.07 622 A I-207

1.07 622 A I-208

1.22 608 A I-209

1.22 608 A I-210

1.29 624 A I-211

1.29 624 A I-212

1.28 688 A I-213

1.28 688 A I-214

1.24 674 A I-215

1.24 674 A I-216

1.04 580 A I-217

1.07 580 A I-218

1.04 580 A I-219

1.18 610 A I-220

1.18 610 A I-221

0.94 594 A I-222

0.94 594 A I-223

1.09 594 A I-224

0.97 584 A I-225

0.97 584 A I-226

1.06 622 A I-227

1.06 622 A I-228

1.10 596 A I-229

1.08 596 A I-230

1.06 630 A I-231

1.07 605 A I-232

1.07 605 A I-233

1.03 587 A I-234

1.03 587 A I-235

1.16 622 A I-236

1.13 608 A I-237

1.24 660 A I-238

1.14 660 A I-239

1.14 660 A I-240

1.06 661 A I-241

1.06 661 A I-242

1.18 594 A I-243

1.18 594 A I-244

0.99 581 A I-245

0.99 581 A I-246

1.14 674 A I-247

1.14 674 A I-248

1.16 674 A I-249

1.16 674 A I-250

1.04 654 A I-251

1.04 654 A I-252

1.04 624 A I-253

1.04 624 A I-254

1.04 642 A I-255

1.04 642 A I-256

1.07 648 A I-257

1.07 648 A I-258

0.99 610 A I-259

1.07 664 A I-260

1.07 664 A I-261

1.02 594 ASynthesis of Further Compounds (I) by Acidic Ester Saponification ofInitially Obtained Compounds (I)Experimental Procedure for the Synthesis of I-262

Compound I-163 (50 mg, 0.109 mmol) is dissolved in MeOH (1 mL) and HCl(37%, 500 μL) is added. The reaction is stirred at 40° C. until HPLC/MSanalysis indicates complete conversion to the desired product. Afteraddition of water and repeated extraction with EtOAc, the crude titlecompound I-262 can be isolated upon removal of the solvents underreduced pressure and purified by reversed phase chromatography.

TABLE 10 # structure t_(ret) [min] [M + H]⁺ HPLC method I-262

1.34 594 A I-263

1.34 594 ASynthesis of Further Compounds (I) by Alternative Ester Saponificationof Initially Obtained Compounds (I)Experimental Procedure for the Synthesis of I-264

Compound I-100 (92 mg, 0.14 mmol) is dissolved in anhydrous DCM and thesolution is cooled to −78° C. At this temperature a solution of BBr₃(0.5 mL; 2 M in DCM) is added dropwise over a period of 5 min. Thecooling bath is removed and the reaction mixture is allowed to warm tort over a period of 1 h. The reaction is quenched by the addition ofMeOH and phases are separated between EtOAc and water. The organic layeris dried with MgSO₄ and solvents are removed under removed pressure. Thecrude material is dissolved in MeOH and aqueous NaOH (4 M) is added. Thereaction mixture is refluxed overnight before it is quenched by theaddition of aqueous HCl. EtOAc is added and the phases are againseparated, dried, concentrated and purified by reversed phase HPLC.

TABLE 11 # structure t_(ret) [min] [M + H]⁺ HPLC method I-264

1.05 610 A I-265

1.05 610 A I-266

1.24 588 A I-267

1.24 588 ASynthesis of Further Compounds (I) by Amidation and HydroxamateFormation of Initially Obtained Compounds (I)Experimental Procedure for the Synthesis of I-268

Compound I-170 (40 mg, 0.067 mmol) is suspended in anhydrous DMF (1 mL)at 0° C. and DIPEA (0.033 mL, 0.2 mmol) and HATU (28.1 mg, 0.074 mmol)are added to the reaction mixture. The reaction mixture is stirred at 0°C. for 30 min. A solution of ammonia (0.011 mL; 7 N in MeOH; 0.074 mmol)is added dropwise. The reaction mixture is stirred for additional 60 minand sat. aq. NH₄Cl solution is added. Deionized water is added and themixture is extracted with a 1:1 mixture of EtOAc and cyclohexane. Thelayers are separated and the organic phase is washed with deionizedwater and dried with MgSO₄.

The solvents are removed under reduced pressure and the crude materialis purified by reversed phase column chromatography.

The following compounds (I) (table 12) are available in an analogousmanner starting from different initially obtained compounds (I).

TABLE 12 # structure t_(ret) [min] [M + H]⁺ HPLC method I-268

1.34 593 A I-269

1.34 593 A I-270

1.37 607 A I-271

1.37 607 A I-272

1.41 621 A I-273

1.41 621 A I-274

1.28 609 A I-275

1.28 609 A I-276

1.35 623 A I-277

1.35 623 A I-278

1.45 637 A I-279

1.45 637 A I-280

1.28 579 A I-281

1.33 647 A I-282

1.33 647 A I-283

1.31 675 A I-284

1.35 659 A I-285

1.22 595 A I-286

1.41 607 A I-287

1.34 593 A I-288

1.21 580 A I-289

1.21 580 ASynthesis of Further Compounds (I) by Derivatization of InitiallyObtained Compounds (I) by SUZUKI ReactionExperimental Procedure for the Synthesis of I-290

Compound I-11 (50 mg, 0.09 mmol). [4-(methoxycarbonyl)phenyl]boronicacid (19.5 mg, 0.108 mmol), Pd(PPh₃)₄ (10.7 mg, 0.1 mmol), and sodiumcarbonate (24 mg, 0.23 mmol) are suspended in a 2:1 mixture of dioxaneand water. The reaction mixture is heated to 130° C. overnight. Afteraddition of EtOAc and water the phases are separated, the organic phaseis dried with MgSO₄ and the solvents are removed under reduced pressure.The crude product is purified by reversed phase column chromatography toyield I-290.

TABLE 13 # structure t_(ret) [min] [M + H]⁺ HPLC method I-290

1.03 594 A I-291

1.03 594 ASynthesis of Further Compounds (I) by Reduction of Initially ObtainedCompounds (I)Experimental Procedure for the Synthesis of I-292

Compound I-88 (330 mg, 0.55 mmol) is dissolved in THF (1 mL) and indiumpowder (254 mg, 2.2 mmol) is added. Conc. HCl (37%, 0.275 mL, 3.325mmol) is added to the reaction mixture and the suspension is allowed tostir 1 h at rt. The reaction mixture is neutralized by the addition ofsat. aq. NaHCO₃ solution and extracted with EtOAc. The organic phase isdried with MgSO₄ and the solvent is removed under reduced pressure.Reversed phase column chromatography yields compound I-292.

The following compounds (I) (table 14) are available in an analogousmanner starting from different initially obtained compounds (I).

TABLE 14 # structure t_(ret) [min] [M + H]⁺ HPLC method I-292

1.28 565 A I-293

1.28 565 A I-294

1.39 569 A I-295

1.39 569 ASynthesis of further compounds (I) by acylation of initially obtainedcompounds (I)Experimental procedure for the synthesis of I-296

To a solution of compound I-292 (30 mg, 0.053 mmol) in THF (5 mL) isadded a solution of AcOH (0.04 mL, 0.08 mmol, 2 M in THF) and DIPEA(22.7 μL, 0.133 mmol). To the reaction mixture a 50% solution of PPA(N-propylphosphonic acid, cyclic trimer) in EtOAc (63 μL; 0.106 mmol) isadded and the solution is allowed to stir at rt overnight. After removalof the solvent under reduced pressure reversed phase columnchromatography yields pure I-296.

The following compounds (I) (table 15) are available in an analogousmanner starting from different initially obtained compounds (I).

TABLE 15 # structure t_(ret) [min] [M + H]⁺ HPLC method I-296

1.37 607 A I-297

1.37 607 A I-298

1.35 593 A I-299

1.35 593 ASynthesis of Further Compounds (I) by Sulfonamidation of InitiallyObtained Compounds (I)Experimental Procedure for the Synthesis of I-300

A solution I-292 (40 mg, 0.071 mmol) in DCM (1 mL) is cooled to −5° C.Pyridine (150 μL) and mesyl chloride (6 μL, 0.071 mmol) are added andthe reaction mixture is allowed to stir for 30 min. The reaction isquenched by the addition of 1N HCl and extracted with EtOAc. Thecombined organic layers are dried with MgSO₄ and the solvents areremoved under reduced pressure. Reversed phase column chromatographygives the desired I-300.

The following compounds (I) (table 16) are available in an analogousmanner starting from initially obtained compounds (I).

TABLE 16 # structure t_(ret) [min] [M + H]⁺ HPLC method I-300

1.38 643 A I-301

1.38 643 A I-302

1.32 647 A I-303

1.32 647 ASynthesis of Further Compounds (I) by Reductive Alkylation of InitiallyObtained Compounds (I)Experimental Procedure for the Synthesis of I-304

Compound I-292 (30 mg, 0.05 mmol) and glyoxylic acid ethyl ester (8.14mg, 0.08 mmol) are dissolved in AcOH (1 mL) and sodiumtriacetoxyborohydride (56 mg, 0.27 mmol) is added. The reaction mixtureis stirred at rt for 15 h before diluted NaHCO₃ is added. EtOAc is addedand the phases are separated. After washing with water the organic phaseis dried with MgSO₄ and the solvents are removed under reduced pressure.Reversed phase column chromatography yields pure I-304.

TABLE 17 # structure t_(ret) [min] [M + H]⁺ HPLC method I-304

1.52 651 A I-305

1.52 651 ASynthesis of Further Compounds (I) by Alkaline Saponification ofInitially Obtained Compounds (I)Experimental Procedure for the Synthesis of I-306

Compound I-304 (23 mg, 0.04 mmol) is dissolved in MeOH (1 mL) andaqueous NaOH solution (0.5 mL, 4 M) is added. The reaction mixture isheated to reflux for 1 h. After acidification with aqueous HCl (2 M) andextraction with EtOAc the organic phase is dried with MgSO₄ andfiltered. Purification with reversed phase HPLC leads to compound I-306.

TABLE 18 # structure t_(ret) [min] [M + H]⁺ HPLC method I-306

1.09 623 A I-307

1.09 623 A

The following Examples describe the biological activity of the compoundsaccording to the invention, without restricting the invention to theseExamples.

Compounds of formulae (I), (Ia) and (Ib) are characterised by their manypossible applications in the therapeutic field. Particular mentionshould be made of those applications in which the inhibiting effect onthe proliferation of cultivated human tumour cells but also on theproliferation of other cells such as endothelial cells, for example, areinvolved.

MDM2-p53 Inhibition AlphaScreen

This assay is used to determine whether the compounds inhibit thep53-MDM2 interaction and thus restore p53 function.

15 μL of compound in 20% DMSO (serial pre-dilutions of compound are donein 100% DMSO) is pipetted to the wells of a white OptiPlate-96(PerkinElmer). A mix consisting of 20 nM GST-MDM2 protein (aa 23-117)and 20 nM biotinylated p53 wt peptide (encompassing aa 16-27 of wt humanp53, amino acid sequence QETFSDLWKLLP-Ttds-Lys-Biotin, molecular weight2132.56 g/mol) is prepared in assay buffer (50 mM Tris/HCl pH 7.2; 120mM NaCl; 0.1% bovine serum albumin (BSA); 5 mM dithiothreitol (DTT); 1mM ethylenediaminetetraacetic acid (EDTA); 0.01% Tween 20). 30 μL of themix is added to the compound dilutions and incubated for 15 min at rtwhile gently shaking the plate at 300 rounds per minute (rpm).Subsequently, 15 μL of premixed AlphaLISA Glutathione Acceptor Beads andAlphaScreen Streptavidin Donor Beads from PerkinElmer (in assay bufferat a concentration of 10 μg/mL each) are added and the samples areincubated for 30 min at rt in the dark (shaking 300 rpm). Afterwards,the signal is measured in a PerkinElmer Envision HTS Multilabel Readerusing the AlphaScreen protocol from PerkinElmer.

Each plate contains negative controls where biotinylated p53-peptide andGST-MDM2 are left out and replaced by assay buffer. Negative controlvalues are entered as low basis value when using the software GraphPadPrism for calculations. Furthermore, a positive control (5% DMSO insteadof test compound; with protein/peptide mix) is pipetted. Determinationof IC₅₀ values are carried out using GraphPad Prism 3.03 software (orupdates thereof).

Table 24 shows the IC₅₀ values of example compounds determined using theabove assay.

TABLE 24 IC₅₀ MDM2 # [nM] I-1 86 I-2 112 I-3 263 I-5 17 I-7 30 I-9 30I-11 462 I-13 272 I-15 152 I-17 324 I-19 240 I-21 64 I-23 290 I-25 324I-27 30 I-37 292 I-39 32 I-40 33 I-43 8 I-63 103 I-69 447 I-71 68 I-7217 I-74 342 I-76 42 I-78 120 I-80 93 I-82 1016 I-84 1176 I-86 159 I-90124 I-92 193 I-112 3293 I-123 38 I-125 347 I-170 11 I-171 4 I-172 302I-173 29 I-175 2132 I-177 16 I-179 71 I-181 92 I-183 10 I-185 3 I-186 2I-188 16 I-190 45 I-192 40 I-194 114 I-196 20 I-198 27 I-200 134 I-20248 I-204 15 I-206 46 I-208 210 I-210 158 I-212 21 I-214 34 I-216 6 I-2175 I-218 460 I-219 31 I-221 7 I-223 271 I-224 17 I-226 12 I-228 11 I-2295 I-230 5 I-231 12 I-233 9 I-235 980 I-236 488 I-237 2 I-238 2 I-2391156 I-240 4 I-242 37 I-244 4 I-246 17 I-248 485 I-250 9 I-252 9 I-254 9I-256 27 I-258 4 I-259 11 I-261 5 I-262 21 I-264 49 I-266 19 I-268 26I-270 27 I-272 25 I-274 20 I-276 46 I-278 33 I-280 7 I-281 67 I-283 4I-284 3 I-285 8 I-286 10 I-287 8 I-288 8 I-290 36 I-292 164 I-296 58I-298 86 I-300 98 I-302 37 I-304 192 I-306 67Cell Proliferation Assays

Cell Titer Glo assay for e.g. SJSA-1, SKOV-3, RS4-11 and KG-1 cells:

SJSA-1 cells (Osteosarcoma, wildtype p53, ATCC CRL-2098TM) are seeded induplicates at day 1 in flat bottom 96 well microtiter plates (whitePackard View Plate 96 well Cat. No. 6005181) in 90 μL RPMI medium, 10%fetal calf serum (FCS, from e.g. JRH Biosciences #12103-500M, Lot.:3N0207) at a density of 2500 cells/well. Any other luminescencecompatible plate format is possible.

Similarly, p53 mutant SKOV-3 cells (ovarian adenocarcinoma, ATCCHTB-77™) are seeded in duplicates in flat bottom 96 well microtiterplates in 90 μL McCoy medium, 10% FCS at a density of 3000 cells/well.

At day 2, 5 μL dilutions of the test compounds covering a concentrationrange between app. 0.6 and 50000 nM are added to the cells. Cells areincubated for three days in a humidified, CO₂-controlled incubator at37° C.

wildtype p53RS4-11 cells (acute lymphoblastic leukemia, ATCC CRL-1873™):

Day 1: RS4-11 cells are seeded in flat bottom 96 well microtiter plates(white Packard View Plate 96 well Cat. No. 6005181) in 90 μL RPMImedium, 10% fetal calf serum (FCS, from e.g. JRH Biosciences#12103-500M, Lot.: 3N0207) at a density of 5000 cells/well. Any otherluminescence compatible plate format is possible.Day 2: 5 μL dilutions of the test compounds covering a concentrationrange between app. 0.3 and 25000 nM (alternative dilution schemes arepossible) are added to the cells. Cells are incubated for three days ina humidified, CO₂ controlled incubator at 37° C. The finalDMSO-concentration is 0.5%.p53 Mutant KG-1 Cells (Acute Myelogenous Leukemia, ATCC CCL-246):Day 1: KG-1 cells harboring a p53 mutation at the exon 6/intron 6 splicedonor site are seeded in flat bottom 96 well microtiter plates (whitePackard View Plate 96 well Cat. No. 6005181) in 90 μL IMDM medium, 10%FCS (JRH Biosciences #12103-500M, Lot.: 3N0207) at a density of 10000cells/well. Any other luminescence compatible plate format is possible.Day 2: 5 μL dilutions of the test compounds covering a concentrationrange between app. 0.3 and 25000 nM (alternative dilution schemes arepossible) are added to the cells. Cells are incubated for three days ina humidified, CO₂ controlled incubator at 37° C. The finalDMSO-concentration is 0.5%.

Evaluation of all Cell Titer Glo assays is done at day 5 after seeding.At day 5, 95 μL of Cell Titer Glo reagent (Cell titer Glo LuminescentCat. No. G7571, Promega) are added to each well and incubated foradditional 10 min at rt (with agitation). Luminescence is measured on aWallac Victor using standard luminescence read out. IC₅₀ values arecalculated using standard Levenburg Marquard algorithms (GraphPadPrism).

In addition, several other cancer cell lines from diverse tissue originsproved to be sensitive to compounds (I), (Ia) and (Ib). Examples includeNCI-H460 (lung), Molp-8 (myeloma) and MV4-11 (AML).

On the basis of their biological properties the compounds of formula(I), (Ia) and (Ib) according to the invention, their tautomers,racemates, enantiomers, diastereomers, mixtures thereof and the salts ofall the above-mentioned forms are suitable for treating diseasescharacterised by excessive or abnormal cell proliferation.

Such diseases include for example: viral infections (e.g. HIV andKaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis,arthritis, Alzheimer's disease, glomerulonephritis and wound healing);bacterial, fungal and/or parasitic infections; leukaemias, lymphomas andsolid tumours (e.g. carcinomas and sarcomas), skin diseases (e.g.psoriasis); diseases based on hyperplasia which are characterised by anincrease in the number of cells (e.g. fibroblasts, hepatocytes, bonesand bone marrow cells, cartilage or smooth muscle cells or epithelialcells (e.g. endometrial hyperplasia); bone diseases and cardiovasculardiseases (e.g. restenosis and hypertrophy). They are also suitable forprotecting proliferating cells (e.g. hair, intestinal, blood andprogenitor cells) from DNA damage caused by radiation, UV treatmentand/or cytostatic treatment.

For example, the following cancers/proliferative diseases may be treatedwith compounds according to the invention, without being restrictedthereto:

brain tumours such as for example acoustic neurinoma, astrocytomas suchas pilocytic astrocytomas, fibrillary astrocytoma, protoplasmicastrocytoma, gemistocytary astrocytoma, anaplastic astrocytoma andglioblastoma, glioma brain lymphomas, brain metastases, hypophysealtumour such as prolactinoma, HGH (human growth hormone) producing tumourand ACTH producing tumour (adrenocorticotropic hormone),craniopharyngiomas, medulloblastomas, meningeomas andoligodendrogliomas; nerve tumours (neoplasms) such as for exampletumours of the vegetative nervous system such as neuroblastomasympathicum, ganglioneuroma, paraganglioma (pheochromocytoma,chromaffinoma) and glomus-caroticum tumour, tumours on the peripheralnervous system such as amputation neuroma, neurofibroma, neurinoma(neurilemmoma, Schwannoma) and malignant Schwannoma, as well as tumoursof the central nervous system such as brain and bone marrow tumours;intestinal cancer such as for example carcinoma of the rectum, coloncarcinoma, colorectal carcinoma, anal carcinoma, carcinoma of the largebowel, tumours of the small intestine and duodenum; eyelid tumours suchas basalioma or basal cell carcinoma; pancreatic cancer or carcinoma ofthe pancreas; bladder cancer or carcinoma of the bladder and otherurothelial cancers; lung cancer (bronchial carcinoma) such as forexample small-cell bronchial carcinomas (oat cell carcinomas) andnon-small cell bronchial carcinomas (NSCLC) such as plate epithelialcarcinomas, adenocarcinomas and large-cell bronchial carcinomas; breastcancer such as for example mammary carcinoma such as infiltrating ductalcarcinoma, colloid carcinoma, lobular invasive carcinoma, tubularcarcinoma, adenocystic carcinoma and papillary carcinoma, hormonereceptor positive breast cancer (estrogen receptor positive breastcancer, progesterone receptor positive breast cancer), Her2 positivebreast cancer, triple negative breast cancer; non-Hodgkin's lymphomas(NHL) such as for example Burkitt's lymphoma, low-malignancynon-Hodgkin's lymphomas (NHL) and mucosis fungoides; uterine cancer orendometrial carcinoma or corpus carcinoma; CUP syndrome (Cancer ofUnknown Primary); ovarian cancer or ovarian carcinoma such as mucinous,endometrial or serous cancer; gall bladder cancer; bile duct cancer suchas for example Klatskin tumour; testicular cancer such as for exampleseminomas and non-seminomas; lymphoma (lymphosarcoma) such as forexample malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas(NHL) such as chronic lymphatic leukaemia, leukaemicreticuloendotheliosis, immunocytoma, plasmocytoma (multiple myeloma,MM), immunoblastoma, Burkitt's lymphoma, T-zone mycosis fungoides,large-cell anaplastic lymphoblastoma and lymphoblastoma; laryngealcancer such as for example tumours of the vocal cords, supraglottal,glottal and subglottal laryngeal tumours; bone cancer such as forexample osteochondroma, chondroma, chondroblastoma, chondromyxoidfibroma, osteoma, osteoid osteoma, osteoblastoma, eosinophilicgranuloma, giant cell tumour, chondrosarcoma, osteosarcoma, Ewing'ssarcoma, reticulo-sarcoma, soft tissue sarcoma, liposarcoma,plasmocytoma, fibrous dysplasia, juvenile bone cysts and aneurysmaticbone cysts; head and neck tumours such as for example tumours of thelips, tongue, floor of the mouth, oral cavity, gums, palate, salivaryglands, throat, nasal cavity, paranasal sinuses, larynx and middle ear;liver cancer such as for example liver cell carcinoma or hepatocellularcarcinoma (HCC); leukaemias, such as for example acute leukaemias suchas acute lymphatic/lymphoblastic leukaemia (ALL), acute myeloidleukaemia (AML); chronic leukaemias such as chronic lymphatic leukaemia(CLL), chronic myeloid leukaemia (CML); stomach cancer or gastriccarcinoma such as for example papillary, tubular and mucinousadenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma,small-cell carcinoma and undifferentiated carcinoma; melanomas such asfor example superficially spreading, nodular, lentigo-maligna andacral-lentiginous melanoma; renal cancer such as for example kidney cellcarcinoma or hypernephroma or Grawitz's tumour; oesophageal cancer orcarcinoma of the oesophagus; penile cancer; prostate cancer (e.g.castration-resistant prostate cancer); throat cancer or carcinomas ofthe pharynx such as for example nasopharynx carcinomas, oropharynxcarcinomas and hypopharynx carcinomas; retinoblastoma, vaginal cancer orvaginal carcinoma, mesothelioma; plate epithelial carcinomas,adenocarcinomas, in situ carcinomas, malignant melanomas and sarcomas;thyroid carcinomas such as for example papillary, follicular andmedullary thyroid carcinoma, as well as anaplastic carcinomas;spinalioma, epidormoid carcinoma and plate epithelial carcinoma of theskin; thymomas, cancer of the urethra, cervical cancer, adenoid cysticcarcinoma (AdCC), adrenocortical carcinoma and cancer of the vulva.

Preferably, the proliferative diseases/cancers to be treated have p53wild-type status.

The new compounds may be used for the prevention, short-term orlong-term treatment of the above-mentioned diseases, optionally also incombination with radiotherapy or other “state-of-the-art” compounds,such as e.g. cytostatic or cytotoxic substances, cell proliferationinhibitors, anti-angiogenic substances, steroids or antibodies.

The compounds of formula (I), (Ia) and (Ib) may be used on their own orin combination with other active substances according to the invention,optionally also in combination with other pharmacologically activesubstances.

Therapeutic agents which may be administered in combination with thecompounds according to the invention, include, without being restrictedthereto, hormones, hormone analogues and antihormones (e.g. tamoxifen,toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide,nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate,finasteride, buserelin acetate, fludrocortisone, fluoxymesterone,medroxy-progesterone, octreotide), aromatase inhibitors (e.g.anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane),LHRH agonists and antagonists (e.g. goserelin acetate, luprolide),inhibitors of growth factors (growth factors such as for example“platelet derived growth factor (PDGF)”, “fibroblast growth factor(FGF)”, “vascular endothelial growth factor (VEGF)”, “epidermal growthfactor (EGF)”, “insulin-like growth factors (IGF)”, “human epidermalgrowth factor (HER, e.g. HER2, HER3, HER4)” and “hepatocyte growthfactor (HGF)”), inhibitors are for example “growth factor” antibodies,“growth factor receptor” antibodies and tyrosine kinase inhibitors, suchas for example cetuximab, gefitinib, imatinib, lapatinib andtrastuzumab); antimetabolites (e.g. antifolates such as methotrexate,raltitrexed, pyrimidine analogues such as 5-fluorouracil (5-FU),capecitabin and gemcitabin, purine and adenosine analogues such asmercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (araC), fludarabine); antitumour antibiotics (e.g. anthracyclins such asdoxorubicin, doxil, daunorubicin, epirubicin and idarubicin,mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin);platinum derivatives (e.g. cisplatin, oxaliplatin, carboplatin);alkylation agents (e.g. estramustin, meclorethamine, melphalan,chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide,temozolomide, nitrosoureas such as for example carmustin and lomustin,thiotepa); antimitotic agents (e.g. Vinca alkaloids such as for examplevinblastine, vindesin, vinorelbin and vincristine; and taxanes such aspaclitaxel, docetaxel); angiogenesis inhibitors (e.g. tasquinimod),tubuline inhibitors; DNA synthesis inhibitors (e.g. sapacitabine), PARPinhibitors, topoisomerase inhibitors (e.g. epipodophyllotoxins such asfor example etoposide and etopophos, teniposide, amsacrin, topotecan,irinotecan, mitoxantrone), serine/threonine kinase inhibitors (e.g. PDK1 inhibitors, B-Raf inhibitors, mTOR inhibitors, mTORC1 inhibitors, PI3Kinhibitors, dual mTOR/PI3K inhibitors, STK 33 inhibitors, AKTinhibitors, PLK 1 inhibitors, inhibitors of CDKs, Aurora kinaseinhibitors), tyrosine kinase inhibitors (e.g. PTK2/FAK inhibitors),protein protein interaction inhibitors (e.g. IAP activator, Mcl-1,MDM2/MDMX), MEK inhibitors (e.g. pimasertib), ERK inhibitors, FLT3inhibitors (e.g. quizartinib), BRD4 inhibitors, IGF-1R inhibitors,TRAILR2 agonists, Bcl-2 inhibitors (e.g. venetoclax), ErbB receptorinhibitors, rapamycin analogs (e.g. everolimus, temsirolimus,ridaforolimus, sirolimus), androgen synthesis inhibitors (e.g.abiraterone, TAK-700), androgen receptor inhibitors (e.g. enzalutamide,ARN-509), immunotherapy (e.g. sipuleucel-T), DNMT inhibitors (e.g. SGI110, temozolomide, vosaroxin), HDAC inhibitors (e.g. vorinostat,entinostat, pracinostat, panobinostat), ANG1/2 inhibitors (e.g.trebananib), CYP17 inhibitors (e.g. galeterone), radiopharmaceuticals(e.g. radium-223, alpharadin), immunotherapeutic agents (e.g.poxvirus-based vaccine, ipilimumab) and various chemotherapeutic agentssuch as amifostin, anagrelid, clodronat, filgrastin, interferon,interferon alpha, leucovorin, rituximab, procarbazine, levamisole,mesna, mitotane, pamidronate and porfimer.

Other possible combination partners are 2-chlorodesoxyadenosine,2-fluorodesoxy-cytidine, 2-methoxyoestradiol, 2C4,3-alethine,131-I-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B,ABT-263/navitoclax, ABT-737, A 105972, A 204197, aldesleukin,alisertib/MLN8237, alitretinoin, allovectin-7, altretamine, alvocidib,amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine,aranose, arglabin, arzoxifene, atamestane, atrasentan, auristatin PE,AVLB, AZ10992, ABX-EGF, AMG-479 (ganitumab), AMG-232, ARRY 162, ARRY438162, ARRY-300, ARRY-142886/AZD-6244 (selumetinib), ARRY-704/AZD-8330,ATSP-7041, AR-12, AR-42, AS-703988, AXL-1717, AZD-1480, AZD-4547,AZD-8055, AZD-5363, AZD-6244, AZD-7762, ARQ-736, ARQ 680, AS-703026(primasertib), avastin, AZD-2014, azacitidine (5-aza), azaepothilone B,azonafide, barasertib/AZD1152, BAY-43-9006, BAY 80-6946, BBR-3464,BBR-3576, bevacizumab, BEZ-235/dactolisib, biricodar dicitrate,birinapant, BCX-1777, BKM-120/buparlisib, bleocin, BLP-25, BMS-184476,BMS-247550, BMS-188797, BMS-275291, BMS-663513, BMS-754807, BNP-1350,BNP-7787, BIBW 2992/afatinib, BIBF 1120/nintedanib, BI 836845, BI 2536,BI 6727/volasertib, BI 836845, BI 847325, BI 853520, BIIB-022,bleomycinic acid, bleomycin A, bleomycin B, brivanib, bryostatin-1,bortezomib, brostallicin, busulphan, BYL-719/alpelisib, CA-4 prodrug,CA-4, cabazitaxel, cabozantinib, CapCell, calcitriol, canertinib,canfosfamide, capecitabine, carboxyphthalatoplatin, CCI-779, CC-115,CC-223, CEP-701, CEP-751, CBT-1 cefixime, ceflatonin, ceftriaxone,celecoxib, celmoleukin, cemadotin, CGM-097, CH4987655/RO-4987655,chlorotrianisene, cilengitide, ciclosporin, CD20 antibodies, CDA-II,CDC-394, CKD-602, CKI-27, clofarabine, colchicin, combretastatin A4, COTinhibitors, CHS-828, CH-5132799, CLL-Thera, CMT-3 cryptophycin 52,CPI-613, CTP-37, CTLA-4 monoclonal antibodies, CP-461, crizotinib,CV-247, cyanomorpholinodoxorubicin, cytarabine, D 24851, dasatinib,decitabine, deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide,desoxyepothilone B, dexamethasone, dexrazoxanet, diethylstilbestrol,diflomotecan, didox, DMDC, dolastatin 10, doranidazole, DS-7423,DS-3032, E7010, E-6201, edatrexat, edotreotide, efaproxiral,eflornithine, EGFR inhibitors, EKB-569, EKB-509, enzastaurin,elesclomol, elsamitrucin, epothilone B, epratuzumab, EPZ-004777,ER-86526, erlotinib, ET-18-OCH3, ethynylcytidine, ethynyloestradiol,exatecan, exatecan mesylate, exemestane, exisulind, fenretinide,figitumumab, floxuridine, folic acid, FOLFOX, FOLFOX4, FOLFIRI,formestane, fostamatinib, fotemustine, galarubicin, gallium maltolate,ganetespib, gefinitib, gemtuzumab, gemtuzumab ozogamicin, gimatecan,glufosfamide, GCS-IOO, GDC-0623, GDC-0941 (pictrelisib), GDC-0980,GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT immunogen, GMK, GMX-1778,GPX-100, gp100-peptide vaccines, GSK-5126766, GSK-690693, GSK-1120212(trametinib), GSK-1995010, GSK-2118436 (dabrafenib), GSK-2126458,GSK-2132231A, GSK-2334470, GSK-2110183, GSK-2141795, GSK-2636771,GSK-525762A/I-BET-762, GW2016, granisetron, herceptine,hexamethylmelamine, histamine, homoharringtonine, hyaluronic acid,hydroxyurea, hydroxyprogesterone caproate, HDM-201, ibandronate,ibritumomab, ibrutinib/PCI-32765, idasanutlin, idatrexate,idelalisib/CAL-101, idenestrol, IDN-5109, IGF-1R inhibitors, IMC-1C11,IMC-A12 (cixutumumab), immunol, indisulam, interferon alpha-2a,interferon alpha-2b, pegylated interferon alpha-2b, interleukin-2,INK-1117, INK-128, INSM-18, ionafarnib, iproplatin, irofulven,isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2,JSF-154, JQ-1, J-107088, conjugated oestrogens, kahalid F, ketoconazole,KW-2170, KW-2450, KU-55933, LCL-161, lobaplatin, leflunomide,lenalidomide, lenograstim, leuprolide, leuporelin, lexidronam, LGD-1550,linezolid, lovastatin, lutetium texaphyrin, lometrexol, lonidamine,losoxantrone, LU 223651, lurbinectedin, lurtotecan, LY-S6AKT1,LY-2780301, LY-2109761/galunisertib, mafosfamide, marimastat,masoprocol, mechloroethamine, MEK inhibitors, MEK-162,methyltestosteron, methylprednisolone, MEDI-573, MEN-10755, MDX-H210,MDX-447, MDX-1379, MGV, midostaurin, minodronic acid, mitomycin,mivobulin, MK-2206, MK-0646 (dalotuzumab), MLN518, MLN-0128, motexafingadolinium, MS-209, MS-275, MX6, neridronate, neratinib, Nexavar,neovastat, nilotinib, nimesulide, nitroglycerin, nolatrexed, norelin,N-acetylcysteine, NU-7441 06-benzylguanine, oblimersen, omeprazole,olaparib, oncophage, oncoVEX^(GM-CSF), ormiplatin, ortataxel, OX44antibodies, OSI-027, OSI-906 (linsitinib), 4-1BB antibodies,oxantrazole, oestrogen, onapristone, palbociclib/PD-0332991,panitumumab, panobinostat, patupilone, pazopanib, pegfilgrastim,PCK-3145, pegfilgrastim, PBI-1402, PBI-05204, PDO325901, PD-1antibodies, PD-616, PEG-paclitaxel, albumin-stabilized paclitaxel,PEP-005, PF-05197281, PF-05212384, PF-04691502, PF-3758309, PHA-665752,PHT-427, P-04, PKC412, P54, PI-88, pelitinib, pemetrexed, pentrix,perifosine, perillylalcohol, pertuzumab, pevonedistat, PI1K inhibitors,PI3K/mTOR inhibitors, PG-TXL, PG2, PLX-4032/RO-5185426 (vemurafenib),PLX-3603/RO-5212054, PT-100, PWT-33597, PX-866, picoplatin,pivaloyloxymethylbutyrate, pixantrone, phenoxodiol 0, PKI166,plevitrexed, plicamycin, polyprenic acid, ponatinib, porfiromycin,posaconazole, prednisone, prednisolone, PRT-062607, quinamed,quinupristin, quizartinib/AC220, R115777, RAF-265, ramosetron,ranpirnase, RDEA-119/BAY 869766, RDEA-436, rebeccamycin analogues,receptor tyrosine kinase (RTK) inhibitors, revimid, RG-7167, RG-7112,RG-7304, RG-7421, RG-7321, RG-7356, RG 7440, RG-7775, rhizoxin, rhu-MAb,rigosertib rinfabate, risedronate, rituximab, robatumumab, rofecoxib,romidepsin, RO-4929097, RO-31-7453, RO-5126766, RO-5068760, RPR 109881A,rubidazone, rubitecan, R-flurbiprofen, RX-0201, ruxolitinib, S-9788,sabarubicin, SAHA, sapacitabine, SAR-405838, sargramostim, satraplatin,SB-408075, SB-431542, Se-015/Ve-015, SU5416, SU6668, SDX-101, selinexor,semustin, seocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747,SR-13668, SRL-172, sorafenib, spiroplatin, squalamine, STF-31,suberanilohydroxamic acid, sutent, T 900607, T 138067, TAE-684, TAK-733,TAS-103, tacedinaline, talaporfin, tanespimycin, Tarceva, tariquitar,tasisulam, taxotere, taxoprexin, tazarotene, tegafur, temozolamide,tesmilifene, testosterone, testosterone propionate, tesmilifene,tetraplatin, tetrodotoxin, tezacitabine, thalidomide, theralux,therarubicin, thymalfasin, thymectacin, tiazofurin, tipifarnib,tirapazamine, tocladesine, tomudex, toremofin, tosedostat, trabectedin,TransMID-107, transretinic acid, traszutumab, tremelimumab, tretinoin,triacetyluridine, triapine, triciribine, trimetrexate, TLK-286TXD 258,tykerb/tyverb, urocidin, valproic acid, valrubicin, vandetanib,vatalanib, vincristine, vinflunine, virulizin, vismodegib, vosaroxin,WX-UK1, WX-554, vectibix, XAV-939, xeloda, XELOX, XL-147, XL-228,XL-281, XL-518/R-7420/GDC-0973, XL-765, YM-511, YM-598, ZD-4190,ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZD1839, ZSTK-474,zoledronat and zosuquidar.

Suitable preparations include for example tablets, pills, capsules,suppositories, lozenges, troches, solutions—particularly solutions forinjection (s.c., i.v., i.m.) and infusion (injectables)—elixirs, syrups,sachets, emulsions, inhalatives or dispersible powders. The content ofthe pharmaceutically active compound(s) should be in the range from 0.1to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole,i.e. in amounts which are sufficient to achieve the dosage rangespecified below. The doses specified may, if necessary, be given severaltimes a day.

Suitable tablets may be obtained, for example, by mixing the activesubstance(s) with known excipients, for example inert diluents such ascalcium carbonate, calcium phosphate or lactose, disintegrants such ascorn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc, agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate, carriers, adjuvants, surfactants. The tablets mayalso comprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinationsthereof according to the invention may additionally contain a sweetenersuch as saccharine, cyclamate, glycerol or sugar and a flavour enhancer,e.g. a flavouring such as vanillin or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions for injection and infusion are prepared in the usual way, e.g.with the addition of isotonic agents, preservatives such asp-hydroxybenzoates, or stabilisers such as alkali metal salts ofethylenediamine tetraacetic acid, optionally using emulsifiers and/ordispersants, whilst if water is used as the diluent, for example,organic solvents may optionally be used as solvating agents ordissolving aids, and transferred into injection vials or ampoules orinfusion bottles.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

The preparations are administered by the usual methods, preferably byoral or transdermal route, most preferably by oral route. For oraladministration the tablets may of course contain, apart from theabove-mentioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

For parenteral use, solutions of the active substances with suitableliquid carriers may be used.

The dosage range of the compounds of formula (I), (Ia) and (Ib)applicable per day is usually from 1 mg to 2000 mg, preferably from 50to 1000 mg, more preferably from 100 to 500 mg.

The dosage for intravenous use is from 1 mg to 1000 mg per hour,preferably between 5 mg and 500 mg per hour.

However, it may sometimes be necessary to depart from the amountsspecified, depending on the body weight, the route of administration,the individual response to the drug, the nature of its formulation andthe time or interval over which the drug is administered. Thus, in somecases it may be sufficient to use less than the minimum dose givenabove, whereas in other cases the upper limit may have to be exceeded.When administering large amounts it may be advisable to divide them upinto a number of smaller doses spread over the day.

The formulation examples which follow illustrate the present inventionwithout restricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet active substance according to formulae (I) or (Ia)or (Ib) 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate  5 mg 500 mg

The finely ground active substance, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size.

B) Tablets per tablet active substance according to formulae (I) or (Ia)or (Ib) 80 mg lactose 55 mg corn starch 190 mg  microcrystallinecellulose 35 mg polyvinylpyrrolidone 15 mg sodiumcarboxymethyl starch 23mg magnesium stearate  2 mg 400 mg 

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. Thesodiumcarboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize.

C) Ampoule solution active substance according to formulae (I) or (Ia)or (Ib) 50 mg sodium chloride 50 mg water for inj.  5 mL

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50mg of active substance.

What is claimed is:
 1. A compound of formula (I)

wherein R¹ is C₁₋₆alkyl, optionally substituted by a group selected fromthe group consisting of C₃₋₆cycloalkyl, phenyl and 5-6 memberedheteroaryl, wherein said C₃₋₆cycloalkyl, phenyl or 5-6 memberedheteroaryl is optionally substituted by one or more, identical ordifferent R^(d1) and/or R^(e1); each R^(d1) is independently selectedfrom the group consisting of —OR^(e1), —NR^(e1)R^(e1), halogen, —CN,—C(O)R^(e1), —C(O)OR^(e1), —C(O)NR^(e1)R^(e1), —S(O)₂R^(e1),—S(O)₂NR^(e1)R^(e1), —NHC(O)R^(e1) and —N(C₁₋₄alkyl)C(O)R^(e1); eachR^(e1) independently of one another denotes hydrogen or a group selectedfrom the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, C₄₋₆cycloalkenyl, phenyl, 5-6 memberedheteroaryl and 3-7 membered heterocyclyl; or R¹ is C₁₋₆ alkoxy-C₁₋₆alkyl or C₁₋₆haloalkyl; R² and R³: one of R² and R³ is hydrogen and theother is selected from the group consisting of phenyl and 5-6 memberedheteroaryl, wherein this phenyl and 5-6 membered heteroaryl isoptionally substituted by one or more, identical or different R^(b2)and/or R^(c2); each R^(b2) is independently selected from the groupconsisting of —OR′, —NR^(c2)R^(c2), halogen, —CN, —C(O)R^(c2),—C(O)OR^(c2), —C(O)NR^(c2)R^(c2), —S(O)₂R^(c2), —S(O)₂NR^(c2)R^(c2),—NHC(O)R^(c2) and —N(C₁₋₄alkyl)C(O)R^(c2); each R^(c2) independently ofone another denotes hydrogen or a group selected from the groupconsisting of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₃₋₆cycloalkyl, C₄₋₆cycloalkenyl, phenyl, 5-6 membered heteroaryl and3-7 membered heterocyclyl; U is NR⁵; R⁵ is a group, optionallysubstituted by one or more, identical or different R^(b4) and/or R^(c4),selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀aryl and 5-10membered heteroaryl; each R^(b4) is independently selected from thegroup consisting of —OR″, —NR^(c4)R^(c4), halogen, —CN, —NO₂,—C(O)R^(c4), —C(O)OR^(c4), —C(O)NR^(c4)R^(c4), —C(O)NR^(g4)OR^(c4),—C(O)C(O)OR^(c4), —S(O)₂R^(c4), —S(O)₂NR^(c4)R^(c4), —NHSO₂R^(c4),—N(C₁₋₄ alkyl)SO₂R^(c4), —NHC(O)R^(c4) and —N(C₁₋₄alkyl)C(O)R^(c4); eachR^(c4) independently of one another denotes hydrogen or a group,optionally substituted by one or more, identical or different R^(d4)and/or R^(e4), selected from the group consisting of C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and3-10 membered heterocyclyl; each R^(d4) is independently selected fromthe group consisting of —OR^(e4), —NR^(e4)R^(e4), halogen, —CN,—C(O)R^(e4), —C(O)OR^(e4), —C(O)NR^(e4)R^(e4), —C(O)NR^(g4)OR^(e4),—OC(O)R^(e4), —S(O)₂R^(e4), —S(O)₂NR^(e4)R^(e4), —NHC(O)R^(e4) and—N(C₁₋₄alkyl)C(O)R^(e4); each R^(e4) independently of one another isselected from the group consisting of hydrogen, C₁₋₆ alkyl,C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10 memberedheterocyclyl; R⁷ is halogen; q denotes the number 1 or 2; W, X and Y iseach CH═ with the proviso that the hydrogen in each CH═ may be replacedby a substituent R⁷; V is oxygen or sulfur; n denotes the number 1, 2 or3; or a salt thereof.
 2. The compound according to claim 1 of formula(Ia)

or a salt thereof.
 3. The compound according to claim 1 wherein one ofR² and R³ is hydrogen and the other is phenyl optionally substituted byone or more, identical or different substituents selected from the groupconsisting of —OC₁₋₆ alkyl, halogen, C₁₋₆alkyl and C₁₋₆haloalkyl; or asalt thereof.
 4. The compound according to claim 1 wherein, R³ ishydrogen; or a salt thereof.
 5. The compound according to claim 1,wherein U is —NH—; or a salt thereof.
 6. The compound according to claim1, wherein V is oxygen; or a salt thereof.
 7. The compound according toclaim 1, wherein n is 1; or a salt thereof.
 8. The compound according toclaim 1, wherein n is 2; or a salt thereof.
 9. A pharmaceuticalcomposition comprising at least one compound according to claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 10. The pharmaceutical composition of claim 9,further comprising at least one other cytostatic or cytotoxic activesubstance.